U.S. patent application number 12/335144 was filed with the patent office on 2009-04-16 for phenylaminopropanol derivatives and methods of their use.
This patent application is currently assigned to Wyeth. Invention is credited to Richard Dale Coghlan, Stephen Todd Cohn, Gavin David Heffernan, Callain Younghee Kim, Paige Erin Mahaney, Michael Anthony Marella, Casey Cameron McComas, Joseph Peter Sabatucci, Eugene Anthony Terefenko, Eugene John Trybulski, An Thien Vu, Fei Ye, Puwen Zhang.
Application Number | 20090099164 12/335144 |
Document ID | / |
Family ID | 34964018 |
Filed Date | 2009-04-16 |
United States Patent
Application |
20090099164 |
Kind Code |
A1 |
Kim; Callain Younghee ; et
al. |
April 16, 2009 |
Phenylaminopropanol Derivatives and Methods of Their Use
Abstract
The present invention is directed to phenylaminopropanol
derivatives of formula I: ##STR00001## or a pharmaceutically
acceptable salt thereof, compositions containing these derivatives,
and methods of their use for the prevention and treatment of
conditions ameliorated by monoamine reuptake including, inter alia,
vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and
genitourinary disorders, chronic fatigue syndrome, fibromylagia
syndrome, nervous system disorders, and combinations thereof,
particularly those conditions selected from the group consisting of
major depressive disorder, vasomotor symptoms, stress and urge
urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and
combinations thereof.
Inventors: |
Kim; Callain Younghee;
(Collegeville, PA) ; Mahaney; Paige Erin;
(Pottstown, PA) ; Trybulski; Eugene John;
(Hungtingdon Valley, PA) ; Zhang; Puwen; (Audubon,
PA) ; Terefenko; Eugene Anthony; (Center Valley,
PA) ; McComas; Casey Cameron; (Phoenixville, PA)
; Marella; Michael Anthony; (Limerick, PA) ;
Coghlan; Richard Dale; (Phoenixville, PA) ;
Heffernan; Gavin David; (Florence, NJ) ; Cohn;
Stephen Todd; (Reading, PA) ; Vu; An Thien;
(Pottstown, PA) ; Sabatucci; Joseph Peter;
(Collegeville, PA) ; Ye; Fei; (Audubon,
PA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP/WYETH
CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
34964018 |
Appl. No.: |
12/335144 |
Filed: |
December 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11091885 |
Mar 28, 2005 |
|
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12335144 |
|
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60557651 |
Mar 30, 2004 |
|
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60569863 |
May 11, 2004 |
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Current U.S.
Class: |
514/230.5 ;
514/235.2; 514/249; 514/254.09; 514/300; 514/339; 514/394; 514/409;
514/415 |
Current CPC
Class: |
C07D 209/42 20130101;
A61P 25/24 20180101; A61P 13/02 20180101; A61P 15/10 20180101; A61P
29/00 20180101; C07D 265/36 20130101; C07D 209/08 20130101; C07D
241/42 20130101; A61P 13/00 20180101; A61P 25/00 20180101; A61P
15/00 20180101; A61P 25/22 20180101; A61P 1/00 20180101; C07D
235/06 20130101; C07D 471/04 20130101; C07D 209/30 20130101; A61P
43/00 20180101 |
Class at
Publication: |
514/230.5 ;
514/254.09; 514/235.2; 514/415; 514/339; 514/249; 514/394; 514/300;
514/409 |
International
Class: |
A61K 31/538 20060101
A61K031/538; A61K 31/496 20060101 A61K031/496; A61K 31/5377
20060101 A61K031/5377; A61K 31/498 20060101 A61K031/498; A61K
31/437 20060101 A61K031/437; A61P 25/24 20060101 A61P025/24; A61P
15/00 20060101 A61P015/00; A61P 1/00 20060101 A61P001/00; A61P
25/22 20060101 A61P025/22; A61P 29/00 20060101 A61P029/00; A61K
31/4184 20060101 A61K031/4184; A61K 31/404 20060101 A61K031/404;
A61K 31/4439 20060101 A61K031/4439 |
Claims
1-28. (canceled)
29. A method for treating or preventing a condition ameliorated by
monoamine reuptake in a subject in need thereof, comprising the
step of: administering to said subject an effective amount of a
compound of formula I: ##STR00221## or a pharmaceutically
acceptable salt thereof; wherein: the dotted line between Y and Z
represents an optional double bond; the dotted line between the two
R.sub.4 groups represents an optional heterocyclic ring of 4 to 6
ring atoms that may be formed between the two R.sub.4 groups,
together with the nitrogen through which they are attached; Y is N,
CR.sub.6, or C.dbd.O; Z is N, NR.sub.7, CR.sub.5, or
C(R.sub.5).sub.2; R.sub.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted
with 0-3 R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl
substituted with 0-3 R.sub.11, heteroaryl substituted with 0-3
R.sub.11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11,; or two adjacent R.sub.1 also represent
methylenedioxy; R.sub.2 is aryl substituted with 0-3 R.sub.1 or
heteroaryl substituted with 0-3 R.sub.1; R.sub.3 is H or
C.sub.1-C.sub.4 alkyl; R.sub.4 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or both R.sub.4 groups, together with the
nitrogen through which they are attached, form a heterocyclic ring
of 4 to 6 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom or
additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3; R.sub.5 is, independently at
each occurrence, H, C.sub.1-C.sub.4 alkyl, aryl substituted with
0-3 R.sub.1, or cyano; or when two R.sub.5 are present, they form a
carbocyclic ring of 3-7 carbons; R.sub.6 is H, C.sub.1-C.sub.4
alkyl, or cyano; R.sub.7 is H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, or aryl substituted with 0-3 R.sub.1;
R.sub.8 is H, or C.sub.1-C.sub.4 alkyl; R.sub.9 is H, or
C.sub.1-C.sub.4 alkyl R.sub.10 is, independently at each
occurrence, H, or C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4
together with the nitrogen to which R.sub.4 is attached form a
nitrogen-containing ring containing 3-6 carbon atoms; n is an
integer from 0 to 4; x is an integer from 1 to 2; and R.sub.11 is
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido; or two adjacent R.sub.11 also
represent methylenedioxy; wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
30. A method according to claim 29, wherein said condition
ameliorated by monoamine reuptake is selected from the group
consisting of vasomotor symptoms, sexual dysfunction,
gastrointestinal and genitourinary disorders, chronic fatigue
syndrome, fibromylagia syndrome, nervous system disorders, and
combinations thereof.
31. A method according to claim 30, wherein said condition
ameliorated by monoamine reuptake is selected from the group
consisting of major depressive disorder, vasomotor symptoms, stress
and urge urinary incontinence, fibromyalgia, pain, diabetic
neuropathy, and combinations thereof.
32. A method for treating or preventing at least one vasomotor
symptom in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of
formula I: ##STR00222## or a pharmaceutically acceptable salt
thereof; wherein: the dotted line between Y and Z represents an
optional double bond; the dotted line between the two R.sub.4
groups represents an optional heterocyclic ring of 4 to 6 ring
atoms that may be formed between the two R.sub.4 groups, together
with the nitrogen through which they are attached; Y is N,
CR.sub.6, or C.dbd.O; Z is N, NR.sub.7, CR.sub.5, or
C(R.sub.5).sub.2; R.sub.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted
with 0-3 R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl
substituted with 0-3 R.sub.11, heteroaryl substituted with 0-3
R.sub.11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy; R.sub.2 is aryl substituted with 0-3 R.sub.1 or
heteroaryl substituted with 0-3 R.sub.1; R.sub.3 is H or
C.sub.1-C.sub.4 alkyl; R.sub.4 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or both R.sub.4 groups, together with the
nitrogen through which they are attached, form a heterocyclic ring
of 4 to 6 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom or
additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3; R.sub.5 is, independently at
each occurrence, H, C.sub.1-C.sub.4 alkyl, aryl substituted with
0-3 R.sub.1, or cyano; or when two R.sub.5 are present, they form a
carbocyclic ring of 3-7 carbons; R.sub.6 is H, C.sub.1-C.sub.4
alkyl, or cyano; R.sub.7 is H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, or aryl substituted with 0-3 R.sub.1;
R.sub.8 is H, or C.sub.1-C.sub.4 alkyl; R.sub.9 is H, or
C.sub.1-C.sub.4 alkyl R.sub.10 is, independently at each
occurrence, H, or C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4
together with the nitrogen to which R.sub.4 is attached form a
nitrogen-containing ring containing 3-6 carbon atoms; n is an
integer from 0 to 4; x is an integer from 1 to 2; and R.sub.11 is
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido; or two adjacent R.sub.11 also
represent methylenedioxy; wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
33. A method according to claim 32, wherein said vasomotor symptom
is hot flush.
34. A method according to claim 33, wherein said subject is
human.
35. A method according to claim 34, wherein said human is a
female.
36. A method according to claim 35, wherein said female is
pre-menopausal.
37. A method according to claim 35, wherein said female is
peri-menopausal.
38. A method according to claim 35, wherein said female is
post-menopausal.
39. A method according to claim 34, wherein said human is a
male.
40. A method according to claim 39, wherein said male is naturally,
chemically or surgically andropausal.
41. A method for treating or preventing at least one depression
disorder in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of
formula I: ##STR00223## or a pharmaceutically acceptable salt
thereof; wherein: the dotted line between Y and Z represents an
optional double bond; the dotted line between the two R.sub.4
groups represents an optional heterocyclic ring of 4 to 6 ring
atoms that may be formed between the two R.sub.4 groups, together
with the nitrogen through which they are attached; Y is N,
CR.sub.6, or C.dbd.O; Z is N, NR.sub.7, CR.sub.5, or
C(R.sub.5).sub.2; R.sub.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted
with 0-3 R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl
substituted with 0-3 R.sub.11, heteroaryl substituted with 0-3
R.sub.11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy; R.sub.2 is aryl substituted with 0-3 R.sub.1 or
heteroaryl substituted with 0-3 R.sub.1; R.sub.3 is H or
C.sub.1-C.sub.4 alkyl; R.sub.4 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or both R.sub.4 groups, together with the
nitrogen through which they are attached, form a heterocyclic ring
of 4 to 6 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom or
additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3, R.sub.5 is, independently at
each occurrence, H, C.sub.1-C.sub.4 alkyl, aryl substituted with
0-3 R.sub.1, or cyano; or when two R.sub.5 are present, they form a
carbocyclic ring of 3-7 carbons; R.sub.6 is H, C.sub.1-C.sub.4
alkyl, or cyano; R.sub.7 is H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, or aryl substituted with 0-3 R.sub.1;
R.sub.8 is H, or C.sub.1-C.sub.4 alkyl; R.sub.2 is H, or
C.sub.1-C.sub.4 alkyl; R.sub.10 is, independently at each
occurrence, H. or C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4
together with the nitrogen to which R.sub.4 is attached form a
nitrogen-containing ring containing 3-6 carbon atoms; n is an
integer from 0 to 4; x is an integer from 1 to 2; and R.sub.11 is
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido; or two adjacent R.sub.11 also
represent methylenedioxy; wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
42. A method according to claim 41, wherein said depression
disorder is major depressive disorder, anxiety, sleep disturbance,
or social phobia.
43. A method according to claim 42, wherein said subject is
human.
44. A method for treating or preventing at least one sexual
dysfunction in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of
formula I: ##STR00224## or a pharmaceutically acceptable salt
thereof; wherein: the dotted line between Y and Z represents an
optional double bond; the dotted line between the two R.sub.4
groups represents an optional heterocyclic ring of 4 to 6 ring
atoms that may be formed between the two R.sub.4 groups, together
with the nitrogen through which they are attached; Y is N,
CR.sub.6, or C.dbd.O; Z is N, NR.sub.7, CR.sub.5, or
C(R.sub.5).sub.2; R.sub.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted
with 0-3 R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl
substituted with 0-3 R.sub.11, heteroaryl substituted with 0-3
R.sub.1, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy; R.sub.2 is aryl substituted with 0-3 R.sub.1 or
heteroaryl substituted with 0-3 R.sub.1; R.sub.3 is H or
C.sub.1-C.sub.4 alkyl; R.sub.4 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or both R.sub.4 groups, together with the
nitrogen through which they are attached, form a heterocyclic ring
of 4 to 6 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom or
additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3; R.sub.5 is, independently at
each occurrence, H, C.sub.1-C.sub.4 alkyl, aryl substituted with
0-3 R.sub.1, or cyano; or when two R.sub.5 are present, they form a
carbocyclic ring of 3-7 carbons; R.sub.6 is H, C.sub.1-C.sub.4
alkyl, or cyano; R.sub.7 is H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, or aryl substituted with 0-3 R.sub.1;
R.sub.8 is H. or C.sub.1-C.sub.4 alkyl; R.sub.2 is H. or
C.sub.1-C.sub.4 alkyl; R.sub.10 is, independently at each
occurrence, H. or C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4
together with the nitrogen to which R.sub.4 is attached form a
nitrogen-containing ring containing 3-6 carbon atoms; n is an
integer from 0 to 4; x is an integer from 1 to 2; and R.sub.11 is
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido; or two adjacent R.sub.11 also
represent methylenedioxy; wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
45. A method according to claim 44, wherein said sexual dysfunction
is desire-related or arousal-related.
46. A method according to claim 45, wherein said subject is
human.
47. A method for treating or preventing pain in a subject in need
thereof, comprising the step of: administering to said subject an
effective amount of a compound of formula I: ##STR00225## or a
pharmaceutically acceptable salt thereof; wherein: the dotted line
between Y and Z represents an optional double bond; the dotted line
between the two R.sub.4 groups represents an optional heterocyclic
ring of 4 to 6 ring atoms that may be formed between the two
R.sub.4 groups, together with the nitrogen through which they are
attached; Y is N, CR.sub.6, or C.dbd.O; Z is N, NR.sub.7, CR.sub.5,
or C(R.sub.5).sub.2; R.sub.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted
with 0-3 R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl
substituted with 0-3 R.sub.11, heteroaryl substituted with 0-3
R.sub.11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.1, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy; R.sub.2 is aryl substituted with 0-3 R.sub.1 or
heteroaryl substituted with 0-3 R.sub.1; R.sub.3 is H or
C.sub.1-C.sub.4 alkyl; R.sub.4 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or both R.sub.4 groups, together with the
nitrogen through which they are attached, form a heterocyclic ring
of 4 to 6 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom or
additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3, R.sub.5 is, independently at
each occurrence, H, C.sub.1-C.sub.4 alkyl, aryl substituted with
0-3 R.sub.1 or cyano; or when two R.sub.5 are present, they form a
carbocyclic ring of 3-7 carbons; R.sub.6 is H, C.sub.1-C.sub.4
alkyl, or cyano; R.sub.7 is H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, or aryl substituted with 0-3 R.sub.1;
R.sub.8 is H, or C.sub.1-C.sub.4 alkyl; R.sub.9 is H, or
C.sub.1-C.sub.4 alkyl; R.sub.10 is, independently at each
occurrence, H, or C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4
together with the nitrogen to which R.sub.4 is attached form a
nitrogen-containing ring containing 3-6 carbon atoms; n is an
integer from 0 to 4; x is an integer from 1 to 2; and R.sub.11 is
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido; or two adjacent R.sub.11 also
represent methylenedioxy; wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
48. A method according to claim 47, wherein said pain is acute
centralized pain, acute peripheral pain, or a combination
thereof.
49. A method according to claim 47, wherein said pain is chronic
centralized pain, chronic peripheral pain, or a combination
thereof.
50. A method according to claim 47, wherein said pain is
neuropathic pain, visceral pain, musculoskeletal pain, bony pain,
cancer pain, inflammatory pain, or a combination thereof.
51. A method according to claim 50, wherein said neuropathic pain
is associated with diabetes, post traumatic pain of amputation,
lower back pain, cancer, chemical injury, toxins, major surgery,
peripheral nerve damage due to traumatic injury compression,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, bums, central pain
conditions related to thalamic conditions, and combinations
thereof.
52. A method according to claim 50, wherein said visceral pain is
associated with ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, and combinations thereof.
53. A method according to claim 47, wherein said pain is
female-specific pain.
54. A method according to claim 47, wherein said subject is human.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Application No.
60/557,651 filed Mar. 30, 2004 and U.S. Application No. 60/569,863
filed May 11, 2004, the entire disclosures of which are herein
incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to phenylaminopropanol
derivatives, compositions containing these derivatives, and methods
of their use for the prevention and treatment of conditions
ameliorated by monoamine reuptake including, inter alia, vasomotor
symptoms (VMS), sexual dysfunction, gastrointestinal and
genitourinary disorders, chronic fatigue syndrome, fibromylagia
syndrome, nervous system disorders, and combinations thereof,
particularly those conditions selected from the group consisting of
major depressive disorder, vasomotor symptoms, stress and urge
urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and
combinations thereof.
BACKGROUND OF THE INVENTION
[0003] Vasomotor symptoms (VMS), referred to as hot flushes and
night sweats, are the most common symptoms associated with
menopause, occurring in 60% to 80% of all women following natural
or surgically-induced menopause. VMS are likely to be an adaptive
response of the central nervous system (CNS) to declining sex
steroids. To date, the most effective therapies for VMS are
hormone-based treatments, including estrogens and/or some
progestins. Hormonal treatments are very effective at alleviating
VMS, but they are not appropriate for all women. It is well
recognized that VMS are caused by fluctuations of sex steroid
levels and can be disruptive and disabling in both males and
females. A hot flush can last up to thirty minutes and vary in
their frequency from several times a week to multiple occurrences
per day. The patient experiences a hot flash as a sudden feeling of
heat that spreads quickly from the face to the chest and back and
then over the rest of the body. It is usually accompanied by
outbreaks of profuse sweating. It may sometimes occur several times
an hour, and it often occurs at night. Hot flushes and outbreaks of
sweats occurring during the night can cause sleep deprivation.
Psychological and emotional symptoms observed, such as nervousness,
fatigue, irritability, insomnia, depression, memory loss, headache,
anxiety, nervousness or inability to concentrate are considered to
be caused by the sleep deprivation following hot flush and night
sweats (Kramer et al., In: Murphy et al., 3.sup.rd Int'l Symposium
on Recent Advances in Urological Cancer Diagnosis and
Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).
[0004] Hot flushes may be even more severe in women treated for
breast cancer for several reasons: 1) many survivors of breast
cancer are given tamoxifen, the most prevalent side effect of which
is hot flush, 2) many women treated for breast cancer undergo
premature menopause from chemotherapy, 3) women with a history of
breast cancer have generally been denied estrogen therapy because
of concerns about potential recurrence of breast cancer (Loprinzi,
et al., Lancet, 2000, 356(9247): 2059-2063).
[0005] Men also experience hot flushes following steroid hormone
(androgen) withdrawal. This is true in cases of age-associated
androgen decline (Katovich, et al., Proceedings of the Society for
Experimental Biology & Medicine, 1990, 193(2): 129-35) as well
as in extreme cases of hormone deprivation associated with
treatments for prostate cancer (Berendsen, et al., European Journal
of Pharmacology, 2001, 419(1): 47-54. As many as one-third of these
patients will experience persistent and frequent symptoms severe
enough to cause significant discomfort and inconvenience.
[0006] The precise mechanism of these symptoms is unknown but
generally is thought to represent disturbances to normal
homeostatic mechanisms controlling thermoregulation and vasomotor
activity (Kronenberg et al., "Thermoregulatory Physiology of
Menopausal Hot Flashes: A Review," Can. J. Physiol. Pharmacol.,
1987, 65:1312-1324).
[0007] The fact that estrogen treatment (e.g. estrogen replacement
therapy) relieves the symptoms establishes the link between these
symptoms and an estrogen deficiency. For example, the menopausal
stage of life is associated with a wide range of other acute
symptoms as described above and these symptoms are generally
estrogen responsive.
[0008] It has been suggested that estrogens may stimulate the
activity of both the norepinephrine (NE) and/or serotonin (5-HT)
systems (J. Pharmacology & Experimental Therapeutics, 1986,
236(3) 646-652). It is hypothesized that estrogens modulate NE and
5-HT levels providing homeostasis in the thermoregulatory center of
the hypothalamus. The descending pathways from the hypothalamus via
brainstem/spinal cord and the adrenals to the skin are involved in
maintaining normal skin temperature. The action of NE and 5-HT
reuptake inhibitors is known to impinge on both the CNS and
peripheral nervous system (PNS). The pathophysiology of VMS is
mediated by both central and peripheral mechanisms and, therefore,
the interplay between the CNS and PNS may account for the efficacy
of dual acting SRI/NR is in the treatment of thermoregulatory
dysfunction. In fact, the physiological aspects and the CNS/PNS
involvement in VMS may account for the lower doses proposed to
treat VMS (Loprinzi, et al., Lancet, 2000, 356:2059-2063; Stearns
et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat
the behavioral aspects of depression. The interplay of the CNS/PNS
in the pathophysiology of VMS and the presented data within this
document were used to support the claims that the norepinephrine
system could be targeted to treat VMS.
[0009] Although VMS are most commonly treated by hormone therapy
(orally, transdermally, or via an implant), some patients cannot
tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3):
155-164, Fink et al., Nature, 1996, 383(6598): 306). In addition,
hormone replacement therapy is usually not recommended for women or
men with or at risk for hormonally sensitive cancers (e.g. breast
or prostate cancer). Thus, non-hormonal therapies (e.g. fluoxetine,
paroxetine [SRIs] and clonidine) are being evaluated clinically.
WO9944601 discloses a method for decreasing hot flushes in a human
female by administering fluoxetine. Other options have been studied
for the treatment of hot flashes, including steroids,
alpha-adrenergic agonists, and beta-blockers, with varying degree
of success (Waldinger et al., Maturitas, 2000, 36(3): 165-168).
[0010] It has been reported that .alpha..sub.2-adrenergic receptors
play a role in thermoregulatory dysfunctions (Freedman et al.,
Fertility & Sterility, 2000, 74(1): 20-3). These receptors are
located both pre- and post-synaptically and mediate an inhibitory
role in the central and peripheral nervous system. There are four
distinct subtypes of the adrenergic.sub..alpha.2 receptors, i.e.,
are .alpha..sub.2A, .alpha..sub.2B, .alpha..sub.2C and
.alpha..sub.2D (Mackinnon et al., TIPS, 1994, 15: 119; French,
Pharmacol. Ther., 1995, 68: 175). It has been reported that a
non-select .alpha..sub.2-adrenoceptor antagonist, yohimbine,
induces a flush and an .alpha..sub.2-adrenergic receptor agonist,
clonidine, alleviates the yohimbine effect (Katovich, et al.,
Proceedings of the Society for Experimental Biology & Medicine,
1990, 193(2): 129-35, Freedman et al., Fertility & Sterility,
2000, 74(1): 20-3). Clonidine has been used to treat hot flush.
However, using such treatment is associated with a number of
undesired side effects caused by high doses necessary to abate hot
flash described herein and known in the related arts.
[0011] Given the complex multifaceted nature of thermoregulation
and the interplay between the CNS and PNS in maintaining
thermoregulatory homeostasis, multiple therapies and approaches can
be developed to target vasomotor symptoms. The present invention
focuses on novel compounds and compositions containing these
compounds directed to these and other important uses.
SUMMARY OF THE INVENTION
[0012] The present invention is directed to phenylaminopropanol
derivatives, compositions containing these derivatives, and methods
of their use for the prevention and treatment of conditions
ameliorated by monoamine reuptake including, inter alia, vasomotor
symptoms (VMS), sexual dysfunction, gastrointestinal and
genitourinary disorders, chronic fatigue syndrome, fibromylagia
syndrome, nervous system disorders, and combinations thereof,
particularly those conditions selected from the group consisting of
major depressive disorder, vasomotor symptoms, stress and urge
urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and
combinations thereof.
[0013] In one embodiment, the present invention is directed to
compounds of formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof;
[0014] wherein:
[0015] the dotted line between Y and Z represents an optional
double bond;
[0016] the dotted line between the two R.sub.4 groups represents an
optional heterocyclic ring of 4 to 6 ring atoms that may be formed
between the two R.sub.4 groups, together with the nitrogen through
which they are attached;
[0017] Y is N, CR.sub.6, or C.dbd.O;
[0018] Z is N, NR.sub.7, CR.sub.5, or C(R.sub.5).sub.2;
[0019] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy;
[0020] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0021] R.sub.3 is H or C.sub.1-C.sub.4 alkyl;
[0022] R.sub.4 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or
[0023] both R.sub.4 groups, together with the nitrogen through
which they are attached, form a heterocyclic ring of 4 to 6 ring
atoms, where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom or additional N atom may
be optionally substituted with C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3;
[0024] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or when two R.sub.5 are present, they form a carbocyclic ring of
3-7 carbons;
[0025] R.sub.6 is H, C.sub.1-C.sub.4 alkyl, or cyano;
[0026] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or aryl substituted with 0-3 R.sub.1;
[0027] R.sub.8 is H, or C.sub.1-C.sub.4 alkyl;
[0028] R.sub.9 is H, or C.sub.1-C.sub.4 alkyl;
[0029] R.sub.10 is, independently at each occurrence, H, or
C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4 together with the
nitrogen to which R.sub.4 is attached form a nitrogen-containing
ring containing 3-6 carbon atoms;
[0030] n is an integer from 0 to 4;
[0031] x is an integer from 1 to 2; and
[0032] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0033] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0034] In yet other embodiments, the present invention is directed
to compositions, comprising:
a. at least one compound of formula I; and b. at least one
pharmaceutically acceptable carrier.
[0035] In another embodiment, the present invention is directed to
methods for treating or preventing a condition ameliorated by
monoamine reuptake in a subject in need thereof, comprising the
step of:
[0036] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0037] The conditions ameliorated by monoamine reuptake include
those selected from the group consisting of vasomotor symptoms,
sexual dysfunction, gastrointestinal and genitourinary disorders,
chronic fatigue syndrome, fibromylagia syndrome, nervous system
disorders, and combinations thereof, particularly those conditions
selected from the group consisting of major depressive disorder,
vasomotor symptoms, stress and urge urinary incontinence,
fibromyalgia, pain, diabetic neuropathy, and combinations
thereof.
[0038] In another embodiment, the present invention is directed to
methods for treating or preventing vasomotor symptoms in a subject
in need thereof, comprising the step of:
[0039] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0040] In yet another embodiment, the present invention is directed
to methods for treating or preventing a depression disorder in a
subject in need thereof, comprising the step of:
[0041] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0042] In yet other embodiments, the present invention is directed
to methods for treating or preventing sexual dysfunction in a
subject in need thereof, comprising the step of:
[0043] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0044] In further embodiments, the present invention is directed to
methods for treating or preventing pain in a subject in need
thereof, comprising the step of:
[0045] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0046] In another embodiment, the present invention is directed to
methods for treating or preventing gastrointestinal or
genitourinary disorder, particularly stress incontinence or urge
urinary incontinence, in a subject in need thereof, comprising the
step of:
[0047] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0048] In another embodiment, the present invention is directed to
methods for treating or preventing chronic fatigue syndrome in a
subject in need thereof, comprising the step of:
[0049] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0050] In another embodiment, the present invention is directed to
methods for treating or preventing fibromylagia syndrome in a
subject in need thereof, comprising the step of:
[0051] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] The invention can be more fully understood from the
following detailed description and the accompanying drawings that
form a part of this application.
[0053] FIG. 1 is an overview of estrogen action on
norepinephrine/serotonin mediated thermoregulation.
[0054] FIG. 2 is a schematic representation of the interactions of
norepinephrine and serotonin and their respective receptors
(5-HT.sub.2a, .alpha..sub.1 and .alpha..sub.2-adrenergic).
DETAILED DESCRIPTION OF THE INVENTION
[0055] The present invention is directed to phenylaminopropanol
derivatives, compositions containing these derivatives, and methods
of their use for the prevention and treatment of conditions
ameliorated by monoamine reuptake including, inter alia, vasomotor
symptoms (VMS), sexual dysfunction, gastrointestinal and
genitourinary disorders, chronic fatigue syndrome, fibromylagia
syndrome, nervous system disorders, and combinations thereof,
particularly those conditions selected from the group consisting of
major depressive disorder, vasomotor symptoms, stress and urge
urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and
combinations thereof.
[0056] The following definitions are provided for the full
understanding of terms and abbreviations used in this
specification.
[0057] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include the plural reference unless the
context clearly indicates otherwise. Thus, for example, a reference
to "an antagonist" includes a plurality of such antagonists, and a
reference to "a compound" is a reference to one or more compounds
and equivalents thereof known to those skilled in the art, and so
forth.
[0058] The abbreviations in the specification correspond to units
of measure, techniques, properties, or compounds as follows: "min"
means minutes, "h" means hour(s), ".mu.L" means microliter(s), "mL"
means milliliter(s), "mM" means millimolar, "M" means molar,
"mmole" means millimole(s), "cm" means centimeters, "SEM" means
standard error of the mean and "IU" means International Units.
".DELTA..degree. C." and .DELTA. "ED.sub.50 value" means dose which
results in 50% alleviation of the observed condition or effect (50%
mean maximum endpoint).
[0059] "Norepinephrine transporter" is abbreviated NET.
[0060] "Human norepinephrine transporter" is abbreviated hNET.
[0061] "Serotonin transporter" is abbreviated SERT.
[0062] "Human serotonin transporter" is abbreviated hSERT.
[0063] "Norepinephrine reuptake inhibitor" is abbreviated NRI.
[0064] "Selective norepinephrine reuptake inhibitor" is abbreviated
SNRI.
[0065] "Serotonin reuptake inhibitor" is abbreviated SRI.
[0066] "Selective serotonin reuptake inhibitor" is abbreviated
SSRI.
[0067] "Norepinephrine" is abbreviated NE.
[0068] "Serotonin is abbreviated 5-HT.
[0069] "Subcutaneous" is abbreviated sc.
[0070] "Intraperitoneal" is abbreviated ip.
[0071] "Oral" is abbreviated po.
[0072] In the context of this disclosure, a number of terms shall
be utilized. The term "treatment" as used herein includes
preventative (e.g., prophylactic), curative or palliative treatment
and "treating" as used herein also includes preventative, curative
and palliative treatment.
[0073] The term "effective amount," as used herein, refers to an
amount effective, at dosages, and for periods of time necessary, to
achieve the desired result with respect to prevention or treatment
of vasomotor symptoms, depression disorders, sexual dysfunction, or
pain. In particular, with respect to vasomotor symptoms, "effective
amount" refers to the amount of compound or composition of
compounds that would increase norepinephrine levels to compensate
in part or total for the lack of steroid availability in subjects
subject afflicted with a vasomotor symptom. Varying hormone levels
will influence the amount of compound required in the present
invention. For example, the pre-menopausal state may require a
lower level of compound due to higher hormone levels than the
peri-menopausal state.
[0074] It will be appreciated that the effective amount of
components of the present invention will vary from patient to
patient not only with the particular compound, component or
composition selected, the route of administration, and the ability
of the components (alone or in combination with one or more
combination drugs) to elicit a desired response in the individual,
but also with factors such as the disease state or severity of the
condition to be alleviated, hormone levels, age, sex, weight of the
individual, the state of being of the patient, and the severity of
the pathological condition being treated, concurrent medication or
special diets then being followed by the particular patient, and
other factors which those skilled in the art will recognize, with
the appropriate dosage ultimately being at the discretion of the
attendant physician. Dosage regimens may be adjusted to provide the
improved therapeutic response. An effective amount is also one in
which any toxic or detrimental effects of the components are
outweighed by the therapeutically beneficial effects.
[0075] Preferably, the compounds of the present invention are
administered at a dosage and for a time such that the number of hot
flushes is reduced as compared to the number of hot flushes prior
to the start of treatment. Such treatment can also be beneficial to
reduce the overall severity or intensity distribution of any hot
flushes still experienced, as compared to the severity of hot
flushes prior to the start of the treatment. With respect to
depression disorders, sexual dysfunction, and pain, the compounds
of the present invention are administered at a dosage and for a
time such that there is the prevention, alleviation, or elimination
of the symptom or condition.
[0076] For example, for an afflicted patient, compounds of formula
I, or a pharmaceutically acceptable salt thereof, may be
administered, preferably, at a dosage of from about 0.1 mg/day to
about 500 mg/day, dosed one or two times daily, more preferably
from about 1 mg/day to about 200 mg/day and most preferably from
about 1 mg/day to 100 mg/day for a time sufficient to reduce and/or
substantially eliminate the number and/or severity of hot flushes
or symptom or condition of the depression disorder, sexual
dysfunction, or pain.
[0077] The terms "component," "composition of compounds,"
"compound," "drug," or "pharmacologically active agent" or "active
agent" or "medicament" are used interchangeably herein to refer to
a compound or compounds or composition of matter which, when
administered to a subject (human or animal) induces a desired
pharmacological and/or physiologic effect by local and/or systemic
action.
[0078] The terms "component", "drug" or "pharmacologically active
agent" or "active agent" or "medicament" are used interchangeably
herein to refer to a compound or compounds or composition of matter
which, when administered to an organism (human or animal) induces a
desired pharmacologic and/or physiologic effect by local and/or
systemic action.
[0079] The term "modulation" refers to the capacity to either
enhance or inhibit a functional property of a biological activity
or process, for example, receptor binding or signaling activity.
Such enhancement or inhibition may be contingent on the occurrence
of a specific event, such as activation of a signal transduction
pathway and/or may be manifest only in particular cell types. The
modulator is intended to comprise any compound, e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein,
preferably small molecule, or peptide.
[0080] As used herein, the term "inhibitor" refers to any agent
that inhibits, suppresses, represses, or decreases a specific
activity, such as serotonin reuptake activity or the norepinephrine
reuptake activity.
[0081] The term "inhibitor" is intended to comprise any compound,
e.g., antibody, small molecule, peptide, oligopeptide, polypeptide,
or protein, preferably small molecule or peptide, that exhibits a
partial, complete, competitive and/or inhibitory effect on
mammalian, preferably the human norepinephrine reuptake or both
serotonin reuptake and the norepinephrine reuptake, thus
diminishing or blocking, preferably diminishing, some or all of the
biological effects of endogenous norepinephrine reuptake or of both
serotonin reuptake and the norepinephrine reuptake.
[0082] Within the present invention, the compounds of formula I may
be prepared in the form of pharmaceutically acceptable salts. As
used herein, the term "pharmaceutically acceptable salts" refers to
salts prepared from pharmaceutically acceptable non-toxic acids,
including inorganic salts, and organic salts. Suitable non-organic
salts include inorganic and organic acids such as acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most
preferably is the hydrochloride salt.
[0083] "Administering," as used herein, means either directly
administering a compound or composition of the present invention,
or administering a prodrug, derivative or analog which will form an
equivalent amount of the active compound or substance within the
body.
[0084] The term "subject" or "patient" refers to an animal
including the human species that is treatable with the
compositions, and/or methods of the present invention. The term
"subject" or "subjects" is intended to refer to both the male and
female gender unless one gender is specifically indicated.
Accordingly, the term "patient" comprises any mammal which may
benefit from treatment or prevention of vasomotor symptoms,
depression disorders, sexual dysfunction, or pain, such as a human,
especially if the mammal is female, either in the pre-menopausal,
peri-menopausal, or post-menopausal period. Furthermore, the term
patient includes female animals including humans and, among humans,
not only women of advanced age who have passed through menopause
but also women who have undergone hysterectomy or for some other
reason have suppressed estrogen production, such as those who have
undergone long-term administration of corticosteroids, suffer from
Cushing's syndrome or have gonadal dysgenesis. However, the term
"patient" is not intended to be limited to a woman.
[0085] The terms "premature menopause" or "artificial menopause"
refer to ovarian failure of unknown cause that may occur before age
40. It may be associated with smoking, living at high altitude, or
poor nutritional status. Artificial menopause may result from
oophorectomy, chemotherapy, radiation of the pelvis, or any process
that impairs ovarian blood supply.
[0086] The term "pre-menopausal" means before the menopause, the
term "peri-menopausal" means during the menopause and the term
"post-menopausal" means after the menopause. "Ovariectomy" means
removal of an ovary or ovaries and can be effected according to
Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.
[0087] "Side effect" refers to a consequence other than the one(s)
for which an agent or measure is used, as the adverse effects
produced by a drug, especially on a tissue or organ system other
then the one sought to be benefited by its administration. In the
case, for example, of high doses of NRIs or NRI/SRI compounds
alone, the term "side effect" may refer to such conditions as, for
example, vomiting, nausea, sweating, and flushes (Janowsky, et al.,
Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
[0088] "Alkyl," as used herein, refers to an optionally
substituted, saturated straight, branched, or cyclic hydrocarbon
having from about 1 to about 20 carbon atoms (and all combinations
and subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 1 to about 8 carbon atoms being
preferred, and with from about 1 to about 4 carbon atoms, herein
referred to as "lower alkyl", being more preferred. Alkyl groups
include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl,
isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl,
adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl.
[0089] "Perfluorinated alkyl," as used herein, refers to an alkyl,
as defined above, in which the hydrogens directly attached to the
carbon atoms are completely replaced by fluorine.
[0090] "Alkenyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more double bonds, wherein
alkyl is as defined herein. Alkenyl groups can be optionally
substituted.
[0091] "Alkynyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more triple bonds, wherein
alkyl is as defined herein. Alkynyl groups can be optionally
substituted.
[0092] "Aryl" as used herein, refers to an optionally substituted,
mono-, di-, tri-, or other multicyclic aromatic ring system having
from about 5 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 10 carbons being preferred.
Non-limiting examples include, for example, phenyl, naphthyl,
anthracenyl, and phenanthrenyl.
[0093] "Heteroaryl," as used herein, refers to an optionally
substituted, mono-, di-, tri-, or other multicyclic aromatic ring
system that includes at least one, and preferably from 1 to about 4
heteroatom ring members selected from sulfur, oxygen and nitrogen.
Heteroaryl groups can have, for example, from about 3 to about 50
carbon atoms (and all combinations and subcombinations of ranges
and specific numbers of carbon atoms therein), with from about 4 to
about 10 carbons being preferred. Non-limiting examples of
heteroaryl groups include, for example, pyrryl, furyl, pyridyl,
1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,
thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
[0094] "Heterocyclic ring," as used herein, refers to a stable 5-
to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic
heterocyclic ring that is saturated, partially unsaturated or
unsaturated (aromatic), and which contains carbon atoms and from 1
to 4 heteroatoms independently selected from the group consisting
of N, O and S and including any bicyclic group in which any of the
above defined heterocyclic rings is fused to a benzene ring. The
nitrogen and sulfur heteroatoms may optionally be oxidized. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. If
specifically noted, a nitrogen atom in the heterocycle may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocycle exceeds one, then these
heteroatoms are not adjacent to one another. It is preferred that
the total number of S and O atoms in the heterocycle is not more
than one. Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl,
.alpha.-, .beta.-, or .gamma.-carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl., oxazolyl, oxazolidinylpyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles
include, but are not limited to, pyridinyl, furanyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl,
1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,
oxindolyl, benzoxazolinyl, or isatinyl. Also included are fused
ring and spiro compounds containing, for example, the above
heterocycles.
[0095] "Alkoxy," as used herein, refers to the group R--O-- where R
is an alkyl group as defined herein.
[0096] "Aryloxy," as used herein, refers to the group R--O-- where
R is an aryl group, as defined herein.
[0097] "Heteroaryloxy," as used herein, refers to the group R--O--
where R is a heteroaryl group, as defined herein.
[0098] "Alkanoyloxy," as used herein, refers to the group
R--C(.dbd.O)--O-- where R is an alkyl group of 1 to 5 carbon
atoms.
[0099] "Alkylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R, where R is alkyl, as defined above.
[0100] "Alkylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R, where R is alkyl, as defined above.
[0101] "Alkylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R, where each R is independently, alkyl, as
defined above or the NR part may also be NH.
[0102] "Phenylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2-phenyl, where R is H or alkyl, as defined
above.
[0103] "Heteroarylmethyloxy," as used herein, refers to
--OCH.sub.2--R, where R is heteroaryl, as defined above.
[0104] "Alkylamido," as used herein, refers to --NR--C(.dbd.O)--R,
where each R is independently, alkyl, as defined above, or the NR
part may also be NH.
[0105] "Phenylamido," as used herein, refers to
--NR--C(.dbd.O)-phenyl, where R is H or alkyl, as defined
above.
[0106] "Halo," as used herein, refers to chloro, bromo, fluoro, and
iodo.
[0107] In one embodiment, the present invention is directed to
compounds of formula I:
##STR00003##
[0108] or a pharmaceutically acceptable salt thereof;
[0109] wherein:
[0110] the dotted line between Y and Z represents an optional
double bond;
[0111] the dotted line between the two R.sub.4 groups represents an
optional heterocyclic ring of 4 to 6 ring atoms that may be formed
between the two R.sub.4 groups, together with the nitrogen through
which they are attached;
[0112] Y is N, CR.sub.6, or C.dbd.O;
[0113] Z is N, NR.sub.7, CR.sub.5, or C(R.sub.5).sub.2;
[0114] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy;
[0115] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0116] R.sub.3 is H or C.sub.1-C.sub.4 alkyl;
[0117] R.sub.4 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl, or
[0118] both R.sub.4 groups, together with the nitrogen through
which they are attached, form a heterocyclic ring of 4 to 6 ring
atoms, where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom or additional N atom may
be optionally substituted with C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3;
[0119] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or when two R.sub.5 are present, they form a carbocyclic ring of
3-7 carbons;
[0120] R.sub.6 is H, C.sub.1-C.sub.4 alkyl, or cyano;
[0121] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or aryl substituted with 0-3 R.sub.1;
[0122] R.sub.8 is H, or C.sub.1-C.sub.4 alkyl;
[0123] R.sub.9 is H, or C.sub.1-C.sub.4 alkyl;
[0124] R.sub.10 is, independently at each occurrence, H, or
C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4 together with the
nitrogen to which R.sub.4 is attached form a nitrogen-containing
ring containing 3-6 carbon atoms;
[0125] n is an integer from 0 to 4;
[0126] x is an integer from 1 to 2; and
[0127] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0128] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N. The dotted line in the ring fused to ring A
represents an optional double bond between Y and Z. The dotted line
between the two R.sub.4 groups represents an optional heterocyclic
ring of 4 to 6 ring atoms that may be formed between the two
R.sub.4 groups, together with the nitrogen through which they are
attached.
[0129] In certain preferred embodiments of compounds of formula I,
Y is N. In certain other preferred embodiments, Y is CR.sub.6,
preferably CH. In certain other preferred embodiments, Y is
C.dbd.O.
[0130] In certain more preferred embodiments, Z is N. In certain
preferred embodiments of compounds of formula I, Z is NR.sub.7. In
certain other more preferred embodiments, Z is CR.sub.5. In yet
certain other more preferred embodiments, Z is C(R.sub.5).sub.2. In
certain even more preferred embodiments, Z is CH, C(CH.sub.3), or
C(CN).
[0131] In certain preferred embodiments of compounds of formula I,
R.sub.1 is, independently at each occurrence, alkyl, preferably
C.sub.1-C.sub.4 alkyl, more preferably methyl. In certain other
preferred embodiments, R.sub.1 is, independently at each
occurrence, alkoxy. In certain other preferred embodiments of
compounds, R.sub.1 is, independently at each occurrence, halo,
preferably F or Cl. In certain other preferred embodiments, R.sub.1
is, independently at each occurrence, CF.sub.3. In certain other
preferred embodiments, R.sub.1 is, independently at each
occurrence, OCF.sub.3. In certain other preferred embodiments,
R.sub.1 is, independently at each occurrence, benzyloxy substituted
with 0-3 R.sub.1. In certain other preferred embodiments, R.sub.1
is, independently at each occurrence, aryloxy substituted with 0-3
R.sup.1. In certain other preferred embodiments, R.sub.1 is,
independently at each occurrence, aryl substituted with 0-3
R.sub.1. In certain other preferred embodiments, R.sub.1 is,
independently at each occurrence, heteroaryl substituted with 0-3
R.sub.1. In certain other preferred embodiments, R.sub.1 is,
independently at each occurrence, hydroxy. In certain other
preferred embodiments, R.sub.1 is, independently at each
occurrence, alkanoyloxy. In certain other preferred embodiments,
R.sub.1 is, independently at each occurrence, methylenedioxy. In
certain other preferred embodiments, R.sub.1 is, independently at
each occurrence, nitro. In certain other preferred embodiments,
R.sub.1 is, independently at each occurrence, nitrile. In certain
other preferred embodiments, R.sub.1 is, independently at each
occurrence, alkenyl. In certain other preferred embodiments,
R.sub.1 is, independently at each occurrence, alkynyl. In certain
other preferred embodiments, R.sub.1 is, independently at each
occurrence, alkylsulfoxide. In certain other preferred embodiments,
R.sub.1 is, independently at each occurrence, phenylsulfoxide
substituted with 0-3 R.sub.1. In certain other preferred
embodiments, R.sub.1 is, independently at each occurrence,
alkylsulfone. In certain other preferred embodiments, R.sub.1 is,
independently at each occurrence, phenylsulfone substituted with
0-3 R.sub.1. In certain other preferred embodiments, R.sub.1 is,
independently at each occurrence, alkylsulfonamide. In certain
other preferred embodiments, R.sub.1 is, independently at each
occurrence, phenylsulfonamide substituted with 0-3 R.sub.1. In
certain other preferred embodiments, R.sub.1 is, independently at
each occurrence, heteroaryloxy substituted with 0-3 R.sub.1. In
certain other preferred embodiments, R.sub.1 is, independently at
each occurrence, heteroarylmethyloxy substituted with 0-3 R.sub.1.
In certain other preferred embodiments, R.sub.1 is, independently
at each occurrence, alkylamido. In certain other preferred
embodiments, R.sub.1 is, independently at each occurrence,
phenylamido substituted with 0-3 R.sub.1.
[0132] In certain preferred embodiments of compounds of formula I,
R.sub.2 is aryl substituted with 0-3 R.sub.1, preferably
substituted with no R.sub.1. In certain preferred embodiments,
R.sub.2 is naphthyl substituted with 0-3 R.sub.1, preferably
substituted with no R.sub.1. In certain preferred embodiments,
R.sub.2 is heteroaryl substituted with 0-3 R.sub.1, preferably
substituted with no R.sub.1.
[0133] In certain preferred embodiments of compounds of formula I,
R.sub.3 is H. In certain other preferred embodiments, R.sub.3 is
C.sub.1-C.sub.4 alkyl, preferably C.sub.1 alkyl.
[0134] In certain preferred embodiments of compounds of formula I,
R.sub.4 is, independently at each occurrence, H. In certain
preferred embodiments, R.sub.4 is, independently at each
occurrence, C.sub.1-C.sub.4 alkyl, preferably C.sub.1-C.sub.3
alkyl, more preferably methyl, ethyl, isopropyl. In certain
preferred embodiments of compounds of formula I, R.sub.4 is,
independently at each occurrence, benzyl. In certain preferred
embodiments, R.sub.4 is, independently at each occurrence,
heteroarylmethyl. In certain preferred embodiments, R.sub.4 is,
independently at each occurrence, cycloheptylmethyl,
cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl.
[0135] In certain preferred embodiments of compounds of formula I,
both R.sub.4 groups, together with the nitrogen through which they
are attached, form a heterocyclic ring of 4 to 6 ring atoms, where
one carbon may be optionally replaced with N, O, S, or SO.sub.2,
and where any carbon ring atom or additional N atom may be
optionally substituted with C.sub.1-C.sub.4 alkyl, F, or CF.sub.3.
In certain more preferred embodiments, both R.sub.4 groups,
together with the nitrogen through which they are attached, form a
pyridine, piperidine, piperazine, piperazine substituted with a
methyl group, or morpholine ring.
[0136] In certain preferred embodiments of compounds of formula I,
R.sub.5 is, independently at each occurrence, H. In certain
preferred embodiments of compounds, R.sub.5 is, independently at
each occurrence, C.sub.1-C.sub.4 alkyl, preferably methyl. In
certain preferred embodiments of compounds, R.sub.5 is,
independently at each occurrence, aryl substituted with 0-3
R.sub.1, preferably phenyl, tolyl, or xylyl. In certain preferred
embodiments, R.sub.5 is, independently at each occurrence,
cyano.
[0137] In certain preferred embodiments of compounds of formula I,
when two R.sub.5 are present, when two R.sub.5 are present, they
form a carbocyclic ring of 3-7 carbons, preferably a cyclopentyl or
cyclohexyl.
[0138] In certain preferred embodiments of compounds of formula I,
R.sub.6 is, independently at each occurrence, H. In certain
preferred embodiments of compounds, R.sub.6 is, independently at
each occurrence, C.sub.1-C.sub.4 alkyl, preferably methyl. In
certain preferred embodiments, R.sub.6 is, independently at each
occurrence, cyano.
[0139] In certain preferred embodiments of compounds of formula I,
R.sub.7 is, independently at each occurrence, H. In certain
preferred embodiments of compounds, R.sub.7 is, independently at
each occurrence, C.sub.1-C.sub.6 alkyl, preferably C.sub.1-C.sub.4
alkyl, more preferably, methyl. In certain preferred embodiments of
compounds, R.sub.7 is, independently at each occurrence,
C.sub.3-C.sub.6 cycloalkyl, preferably, cyclopentyl or cyclohexyl.
In certain preferred embodiments of compounds, R.sub.5 is,
independently at each occurrence, aryl substituted with 0-3
R.sub.1, preferably phenyl, tolyl, or xylyl.
[0140] In certain preferred embodiments of compounds of formula I,
R.sub.8 is, independently at each occurrence, H. In certain
preferred embodiments of compounds, R.sub.8 is, independently at
each occurrence, C.sub.1-C.sub.4 alkyl, preferably methyl.
[0141] In certain preferred embodiments of compounds of formula I,
R.sub.9 is, independently at each occurrence, H. In certain
preferred embodiments of compounds, R.sub.9 is, independently at
each occurrence, C.sub.1-C.sub.4 alkyl, preferably methyl.
[0142] In certain preferred embodiments of compounds of formula I,
R.sub.10 is, independently at each occurrence, H. In certain
preferred embodiments of compounds, R.sub.10 is, independently at
each occurrence, C.sub.1-C.sub.4 alkyl, preferably methyl. In
certain preferred embodiments of compounds of formula I, R.sub.10
and R.sub.4 together with the nitrogen to which R.sub.4 is attached
form a nitrogen-containing ring containing 3-6 carbon atoms,
especially, pyrrolidinyl, pyrrolyl, piperidinyl, pyridinyl,
azepanyl, and azepinyl.
[0143] In certain preferred embodiments of compounds of formula I,
n is an integer from 0 to 3. More preferably, n is 0 to 2. Even
more preferably, n is 0 to 1. Yet more preferably, n is 0.
[0144] In certain preferred embodiments of compounds of formula I,
x is an integer from 1 to 2. More preferably, x is 1.
[0145] In certain preferred embodiments of compounds of formula I,
1-2 carbon atoms in ring A may optionally be replaced with N. In
certain preferred embodiments of compounds, one carbon atom in ring
A may optionally be replaced with N. In certain preferred
embodiments, no carbon atoms in ring A are replaced with N.
[0146] In certain preferred embodiments of compounds of formula
I,
[0147] Y is N, CR.sub.6, or C.dbd.O;
[0148] Z is N, NR.sub.7, CR.sub.5, or C(R.sub.5).sub.2;
[0149] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy;
[0150] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0151] R.sub.3 is H
[0152] R.sub.4 is, independently at each occurrence, H, or
C.sub.1-C.sub.4 alkyl,
[0153] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or when two R.sub.5 are present, they form a carbocyclic ring of
3-7 carbons;
[0154] R.sub.6 is H, C1-C4 alkyl, or cyano;
[0155] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, aryl substituted with 0-3 R.sub.1;
[0156] R.sub.8 is H;
[0157] R.sub.9 is H;
[0158] R.sub.10 is H;
[0159] n is an integer from 0 to 4;
[0160] x is 1;
[0161] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0162] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0163] In certain preferred embodiments of compounds of formula
I,
[0164] Y is CR.sub.6;
[0165] Z is CR.sub.5;
[0166] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy;
[0167] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0168] R.sub.3 is H or C.sub.1-C.sub.4 alkyl;
[0169] R.sub.4 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl;
[0170] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or when two R.sub.5 are present, they form a carbocyclic ring of
3-7 carbons;
[0171] R.sub.6 is H, C.sub.1-C.sub.4 alkyl, or cyano;
[0172] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or aryl substituted with 0-3 R.sub.1;
[0173] R.sub.8 is H or C.sub.1-C.sub.4 alkyl;
[0174] R.sub.9 is H or C.sub.1-C.sub.4 alkyl;
[0175] R.sub.10 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4, together with the
nitrogen to which R.sub.4 is attached, form a nitrogen-containing
ring containing 3-6 carbon atoms;
[0176] n is an integer from 0 to 4;
[0177] x is an integer from 1 to 2; and
[0178] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0179] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0180] In certain preferred embodiments of compounds of formula
I,
[0181] Y is CR.sub.6;
[0182] Z is C(R.sub.5).sub.2;
[0183] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.11 also represent
methylenedioxy;
[0184] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0185] R.sub.3 is H or C.sub.1-C.sub.4 alkyl;
[0186] R.sub.4 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl;
[0187] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or when two R.sub.5 are present, they form a carbocyclic ring of
3-7 carbons;
[0188] R.sub.6 is H, C.sub.1-C.sub.4 alkyl, or cyano;
[0189] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or aryl substituted with 0-3 R.sub.1;
[0190] R.sub.8 is H or C.sub.1-C.sub.4 alkyl;
[0191] R.sub.9 is H or C.sub.1-C.sub.4 alkyl;
[0192] R.sub.10 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4, together with the
nitrogen to which R.sub.4 is attached, form a nitrogen-containing
ring containing 3-6 carbon atoms;
[0193] n is an integer from 0 to 4;
[0194] x is an integer from 1 to 2; and
[0195] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0196] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0197] In certain preferred embodiments of compounds of formula
I,
[0198] Y is C.dbd.O;
[0199] Z is C(R.sub.5).sub.2;
[0200] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.1 also represent
methylenedioxy;
[0201] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0202] R.sub.3 is H or C.sub.1-C.sub.4 alkyl;
[0203] R.sub.4 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl;
[0204] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or when two R.sub.5 are present, they form a carbocyclic ring of
3-7 carbons;
[0205] R.sub.6 is H, C.sub.1-C.sub.4 alkyl, or cyano;
[0206] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or aryl substituted with 0-3 R.sub.1;
[0207] R.sub.8 is H or C.sub.1-C.sub.4 alkyl;
[0208] R.sub.9 is H or C.sub.1-C.sub.4 alkyl;
[0209] R.sub.10 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4, together with the
nitrogen to which R.sub.4 is attached, form a nitrogen-containing
ring containing 3-6 carbon atoms;
[0210] n is an integer from 0 to 4;
[0211] x is an integer from 1 to 2; and
[0212] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0213] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0214] In certain preferred embodiments of compounds of formula
I,
[0215] Y is C.dbd.O;
[0216] Z is NR.sub.7;
[0217] R.sub.1 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, arylalkyloxy substituted with 0-3
R.sub.11, aryloxy substituted with 0-3 R.sub.11, aryl substituted
with 0-3 R.sub.11, heteroaryl substituted with 0-3 R.sub.11,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, phenylsulfoxide substituted with 0-3 R.sub.11,
alkylsulfone, phenylsulfone substituted with 0-3 R.sub.11,
alkylsulfonamide, phenylsulfonamide substituted with 0-3 R.sub.11,
heteroaryloxy substituted with 0-3 R.sub.11, heteroarylmethyloxy
substituted with 0-3 R.sub.11, alkylamido, or arylamido substituted
with 0-3 R.sub.11; or two adjacent R.sub.11 also represent
methylenedioxy;
[0218] R.sub.2 is aryl substituted with 0-3 R.sub.1 or heteroaryl
substituted with 0-3 R.sub.1;
[0219] R.sub.3 is H or C.sub.1-C.sub.4 alkyl;
[0220] R.sub.4 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, arylalkyl, heteroarylmethyl,
cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or
cyclobutylmethyl;
[0221] R.sub.5 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sub.1, or cyano;
or in the cases where two R.sub.5 substitutions are present, they
may form a carbocyclic ring of C.sub.3-C.sub.7;
[0222] R.sub.6 is H, C.sub.1-C.sub.4 alkyl, or cyano;
[0223] R.sub.7 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or aryl substituted with 0-3 R.sub.1;
[0224] R.sub.8 is H or C.sub.1-C.sub.4 alkyl;
[0225] R.sub.9 is H or C.sub.1-C.sub.4 alkyl;
[0226] R.sub.10 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; R.sub.10 is, independently at each
occurrence, H or C.sub.1-C.sub.4 alkyl; or R.sub.10 and R.sub.4,
together with the nitrogen to which R.sub.4 is attached, form a
nitrogen-containing ring containing 3-6 carbon atoms;
[0227] n is an integer from 0 to 4;
[0228] x is an integer from 1 to 2; and
[0229] R.sub.11 is alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
two adjacent R.sub.11 also represent methylenedioxy;
[0230] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0231] Preferred compounds of formula I include: [0232]
1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol;
[0233]
1-(5-fluoro-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol-
; [0234] 1-(1H-indol-1-yl)-3-morpholin-4-yl-1-phenylpropan-2-ol;
[0235] 3-(dimethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0236] 3-(ethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol; [0237]
1-(1H-indol-1-yl)-3-(isopropylamino)-1-phenylpropan-2-ol; [0238]
3-(benzylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol; [0239]
3-[(cyclohexylmethyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0240]
3-[(cyclohexylmethyl)amino]-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-o-
l; [0241]
3-(isopropylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-o-
l; [0242] 1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0243]
3-(ethylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0244] 1-(1H-indol-1-yl)-1-phenyl-3-piperazin-1-ylpropan-2-ol di;
[0245]
1-(1H-indol-1-yl)-1-phenyl-3-[(pyridin-4-ylmethyl)amino]propan-2-ol;
[0246]
1-(5-chloro-1H-indol-1-yl)-1-phenyl-3-piperidin-1-ylpropan-2-ol;
[0247] 1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0248] 3-amino-1-(1H-indol-1-yl)-1-phenylpropan-2-ol; [0249]
3-(ethylamino)-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0250] 3-amino-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0251]
1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0252]
3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0253] 1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0254] 1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0255] 3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0256]
3-[ethyl(methyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0257]
1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0258]
1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-1-ol;
[0259]
1-[2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-3-carbon
itrile; [0260]
1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol; [0261]
1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol; [0262]
3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0263]
1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0264]
1-(4-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0265]
1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy)phenyl]propan-2--
ol; [0266]
1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl-
]propan-2-ol; [0267]
1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]propan-2--
ol; [0268]
1-(2-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol- ;
[0269]
1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]p-
ropan-2-ol; [0270]
1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]propan-2--
ol; [0271]
1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl-
]propan-2-ol; [0272]
4-amino-1-(3-chlorophenyl)-1-(1H-indol-1-yl)butan-2-ol [0273]
1-(3-bromophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0274]
3-[2-hydroxy-1-(1H-indol-1-yl)-3-(methylamino)propyl]benzonitrile
[0275]
1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0276]
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-methylphenyl)-1H-indol-1-yl]pr-
opan-2-ol; [0277]
1-(4-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)propan-2-ol;
[0278]
1-(2-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0279]
1-(4-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0280]
1-(1H-indol-1-yl)-3-(methylamino)-1-(3-methylphenyl)propan-2-ol;
[0281]
1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol;
[0282]
1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol;
[0283]
3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol;
[0284]
1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-morpholin-4-ylpropan-2-ol;
[0285]
1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(propylamino)propan-2-ol;
[0286]
1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)pro-
pan-2-ol; [0287]
1-(1H-indol-1-yl)-3-(methylamino)-1-(4-methylphenyl)propan-2-ol;
[0288]
1-(2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2--
ol; [0289]
1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2--
ol; [0290]
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(2-methylphenyl)-1H-ind-
ol-1-yl]propan-2-ol; [0291]
1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indol-1-yl)-
propan-2-ol; [0292]
1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3--
(methylamino)propan-2-ol; [0293]
1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phe-
nylpropan-2-ol; [0294]
3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indol-1-yl)-1-phenylpropan-2-o-
l; [0295]
1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-in-
dol-1-yl)propan-2-ol; [0296]
1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indol-1-yl)-
propan-2-ol; [0297]
1-(1H-indol-1-yl)-1-(3-methoxyphenyl)-3-(methylamino)propan-2-ol;
[0298]
1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-ol;
[0299]
3-(methylamino)-1-(2-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0300]
1-(1H-benzimidazol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0301]
3-(methylamino)-1-(2-methyl-1H-benzimidazol-1-yl)-1-phenylpropan-2-ol;
[0302]
1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0303]
1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0304]
1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0305]
1-(7-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0306]
1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0307]
1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0308]
1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0309]
1-(3-fluorophenyl)-1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)prop-
an-2-ol; [0310]
3-(methylamino)-1-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol;
[0311]
1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methy-
lamino)propan-2-ol; [0312]
3-(methylamino)-1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-1-yl)propan-2-ol;
[0313]
1-(5-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0314]
3-(methylamino)-1-(3-fluorophenyl)-1-(1H-pyrrolo[2,3-c]pyridin-1-yl)propa-
n-2-ol; [0315]
1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-o-
l; [0316]
3-(methylamino)-1-(6-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0317]
3-(methylamino)-1-(7-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0318]
1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)propa-
n-2-ol; [0319]
1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)propan-2-ol;
[0320]
3-(methylamino)-1-(4-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0321]
3-(methylamino)-1-(5-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0322]
1-(3-fluorophenyl)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)propa-
n-2-ol; [0323]
1-(3-ethyl-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;
[0324]
1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indol-1-yl)propa-
n-2-ol; [0325]
7-fluoro-1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dih-
ydro-2H-indol-2-one; [0326]
1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-i-
ndol-2-one; [0327]
7-fluoro-1-[1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimet-
hyl-1,3-dihydro-2H-indol-2-one; [0328]
1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol; [0329]
1(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol; [0330]
1'-[2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3'-indol-
]-2'(1'H)-one; [0331]
2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethanol;
[0332]
2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[pyrrolidin-2-yl]ethanol;
[0333]
1'-[2hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclobutane-1,3'-
-indol]-2'(1'H)-one; [0334]
1'-[2hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclopentane-1,3'-indol-
]-2'(1'H)-one; [0335]
1'-[2hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclopropane-1,3'-indol-
]-2'(1'H)-one; [0336]
5-fluoro-1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dih-
ydro-2H-indol-2-one; [0337]
3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol;
[0338]
7'-fluoro-1'-[2hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cycloh-
exane-1,3'-indol]-2'(1'H)-one; [0339]
5'-bromo-1'-[2hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,-
3'-indol]-2'(1'H)-one; [0340]
1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indol-1-yl]-3-(methylamino)pr-
opan-2-ol; [0341]
1-[3-(3,4-dichlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methylamin-
o)propan-2-ol; [0342]
1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indol-1-yl]-3-(methylamino)pr-
opan-2-ol; [0343]
1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0344]
3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0345]
1-(5-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol; [0346]
3-amino-1-(5-chloro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0347]
[3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]methylamine-
; [0348]
1-(7-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol; [0349]
[3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]methylamine-
; [0350]
1-(4-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0351]
1-(4-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-
-2-ol; [0352]
1-(5-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0353]
1-(5-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;
[0354]
1-[2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-4-carbon
itrile; [0355]
1-(6-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0356]
1-[2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-5-carbonitrile;
[0357]
1-[1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1H-indole-4-
-carbonitrile; [0358]
1-(6-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;
[0359]
1-(6-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0360]
3-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol; [0361]
1-(7-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-
-2-ol; [0362]
1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl)phenyl]propan-2-o-
l; [0363]
1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclohexane-1,3'-indo-
l]-1 '(2'H)-ylpropan-2-ol; [0364]
1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl)pheny-
l]propan-2-ol; [0365]
1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0366]
1-(3,4-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0367]
1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)propa-
n-2-ol; [0368]
1-(4-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0369]
1-(6-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0370]
1-(7-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0371]
1-(7-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;
[0372]
1-(4-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0373]
1-(6-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;
[0374]
1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0375]
1-(5-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0376]
1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0377]
1-(3-fluorophenyl)-1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)propan-2--
ol; [0378]
1-(3,5-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan--
2-ol; [0379]
1-(3,5-difluorophenyl)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)propa-
n-2-ol; [0380]
4-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)butan-2-ol; [0381]
1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(m-
ethylamino)propan-2-ol; [0382]
1-(3,5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(meth-
ylamino)propan-2-ol; [0383]
1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol; [0384]
1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indol-1-yl)-
propan-2-ol; [0385]
1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclopentane-1,3'-indol]-1
'(2'H)-ylpropan-2-ol; [0386]
1-(3-fluorophenyl)-1-[3-(4-methoxyphenyl)-1H-indol-1-yl]-3-(methylamino)p-
ropan-2-ol; [0387]
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-methylphenyl)-1H-indol-1-yl]pr-
opan-2-ol; [0388]
1-[3-(4-tert-butylphenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methylamin-
o)propan-2-ol; [0389]
1-(3-fluorophenyl)-1-[3-(3-methoxyphenyl)-1H-indol-1-yl]-3-(methylamino)p-
ropan-2-ol; [0390]
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl)phenyl]-1H-in-
dol-1-yl}propan-2-ol; [0391]
1-(3,5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-3-(methylam-
ino)propan-2-ol; [0392]
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl)phenyl]-1H-in-
dol-1-yl}propan-2-ol; [0393]
1-(3-fluorophenyl)-1-[3-(2-methoxyphenyl)-1H-indol-1-yl]-3-(methylamino)p-
ropan-2-ol; [0394]
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl)phenyl]-1H-in-
dol-1-yl}propan-2-ol; [0395]
3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol; [0396]
1-(7-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0397]
3-amino-1-(7-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0398]
1-(7-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0399]
1-(4-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0400]
1-(7-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0401]
1-(4-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol;
[0402]
1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indol-
-1-yl]propan-2-ol; [0403]
1-(6-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0404]
3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indol-1-yl]propan-2-ol-
; [0405]
3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indol-1-yl]pro-
pan-2-ol; [0406]
1-(3-tert-butyl-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-
-ol; [0407]
1-(1H-indol-1-yl)-2-methyl-3-(methylamino)-1-phenylpropan-2-ol;
[0408] 3-(1H-indol-1-yl)-1-(methylamino)-3-phenylbutan-2-ol; [0409]
1-tert-butyl-3-[2hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-b-
enzimidazol-2-one; [0410]
1-[2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-propyl-1,3-dihydro-2H-benz-
imidazol-2-one; [0411]
5-bromo-1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dihy-
dro-2H-indol-2-one; [0412]
6-fluoro-1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dih-
ydro-2H-indol-2-one; [0413]
4-fluoro-1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dih-
ydro-2H-indol-2-one; [0414]
1-cyclobutyl-3-[2hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-b-
enzimidazol-2-one; [0415]
5-fluoro-3-[2hydroxy-3-(methylamino)-1-phenylpropyl]-1-propyl-1,3-dihydro-
-2H-benzimidazol-2-one; [0416]
1-ethyl-3-[1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1,3-dihydr-
o-2H-benzimidazol-2-one; [0417]
1-ethyl-3-[2hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzim-
idazol-2-one; [0418]
4-fluoro-3-[2hydroxy-3-(methylamino)-1-phenylpropyl]-1-isopropyl-1,3-dihy-
dro-2H-benzimidazol-2-one;
[0419]
1-cyclopentyl-3-[2hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihy-
dro-2H-benzimidazol-2-one; [0420]
1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3-isopropyl-1,3-dihydro-2H-be-
nzimidazol-2-one; [0421]
3-[3(ethylamino)-2-hydroxy-1-phenylpropyl]-5-fluoro-1-isopropyl-1,3-dihyd-
ro-2H-benzimidazol-2-one; [0422]
1-[2hydroxy-3-(methylamino)-1-phenylpropyl]-3-methyl-1,3-dihydro-2H-benzi-
midazol-2-one; [0423]
1-ethyl-5-fluoro-3-[2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-
-2H-benzimidazol-2-one; [0424]
1-ethyl-4-fluoro-3-[2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-
-2H-benzimidazol-2-one; [0425]
4-fluoro-3-[1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1-isoprop-
yl-1,3-dihydro-2H-benzimidazol-2-one; [0426]
1-ethyl-4-fluoro-3-[2hydroxy-3-(methylamino)-1-(3-fluorophenyl)-propyl]-1-
,3-dihydro-2H-benzimidazol-2-one; [0427]
1-[1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimethyl-1,3-d-
ihydro-2H-indol-2-one; [0428]
1-[3-(2,3-difluorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methylamin-
o)propan-2-ol; [0429]
1-[3-(2-chlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methylamino)pr-
opan-2-ol; and
[0430] pharmaceutically acceptable salts thereof, particularly
hydrochloride and dihydrochloride salts thereof.
[0431] Particularly preferred compounds of formula I include:
[0432]
(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-o-
l; [0433]
(1RS,2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)--
1-phenylpropan-2-ol; [0434]
(1RS,2SR)-1-(1H-indol-1-yl)-3-morpholin-4-yl-1-phenylpropan-2-ol;
[0435]
(1RS,2SR)-3-(dimethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0436]
(1RS,2SR)-3-(ethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0437]
(1RS,2SR)-1-(1H-indol-1-yl)-3-(isopropylamino)-1-phenylpropan-2-ol;
[0438]
(1RS,2SR)-3-(benzylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0439]
(1RS,2SR)-3-[(cyclohexylmethyl)amino]-1-(1H-indol-1-yl)-1-phenylpr-
opan-2-ol; [0440]
(1RS,2SR)-3-[(cyclohexylmethyl)amino]-1-(3-methyl-1H-indol-1-yl)-1-phenyl-
propan-2-ol; [0441]
(1RS,2SR)-3-(isopropylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2--
ol; [0442]
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol- ;
[0443]
(1RS,2SR)-3-(ethylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropa-
n-2-ol; [0444]
(1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-piperazin-1-ylpropan-2-ol;
[0445]
(1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-[(pyridin-4-ylmethyl)amino]propan--
2-ol; [0446]
(1RS,2SR)-1-(5-chloro-1H-indol-1-yl)-1-phenyl-3-piperidin-1-ylpropan-2-ol-
; [0447]
(1RS,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0448] (1RS,2SR)-3-amino-1-(1H-indol-1-yl)-1-phenylpropan-2-ol;
[0449]
(1RS,2SR)-3-(ethylamino)-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0450]
(1RS,2SR)-3-amino-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0451]
(1RS,2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol; [0452]
(1RS,2SR)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0453]
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0454]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0455]
(1RS,2SR)-3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0456]
(1RS,2SR)-3-[ethyl(methyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan--
2-ol; [0457]
(1RS,2SR)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0458]
(1RS,2RS)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-1-ol; [0459]
1-[(1RS,2SR)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-3-carbon-
itrile; [0460]
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0461]
(1S,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0462]
(1S,2R)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0463]
(1S,2R)-1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-
-2-ol; [0464]
(1S,2R)-1-(4-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0465]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy)p-
henyl]propan-2-ol; [0466]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]p-
ropan-2-ol; [0467]
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]p-
ropan-2-ol; [0468]
(1S,2R)-1-(2-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0469]
(1SR,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy-
)phenyl]propan-2-ol; [0470]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]p-
ropan-2-ol; [0471]
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]p-
ropan-2-ol; [0472]
(1S,2R)-4-amino-1-(3-chlorophenyl)-1-(1H-indol-1-yl)butan-2-ol
[0473]
(1S,2R)-1-(3-bromophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0474]
3-[(1S,2R)-2-hydroxy-1-(1H-indol-1-yl)-3-(methylamino)propyl]benzo-
nitrile [0475]
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0476]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-methylphenyl)-1-
H-indol-1-yl]propan-2-ol; [0477]
(1S,2R)-1-(4-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)prop-
an-2-ol; [0478]
(1S,2R)-1-(2-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0479]
(1S,2R)-1-(4-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-
-2-ol; [0480]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(3-methylphenyl)propan-2-ol;
[0481]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-
-2-ol; [0482]
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol;
[0483]
(1S,2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan--
2-ol; [0484]
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-morpholin-4-ylpropan-2-ol;
[0485]
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(propylamino)propan-
-2-ol; [0486]
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)pr-
opan-2-ol; [0487]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(4-methylphenyl)propan-2-ol;
[0488]
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methyl-
amino)propan-2-ol; [0489]
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol-
; [0490]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(2-methylphenyl)--
1H-indol-1-yl]propan-2-ol; [0491]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol; [0492]
(1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluoroph-
enyl)-3-(methylamino)propan-2-ol; [0493]
(1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamin-
o)-1-phenylpropan-2-ol; [0494]
(1S,2R)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indol-1-yl)-1-phenylpr-
opan-2-ol; [0495]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol; [0496]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol; [0497]
(1S,2R)-1-(1H-indol-1-yl)-1-(3-methoxyphenyl)-3-(methylamino)propan-2-ol;
[0498]
(1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)pro-
pan-2-ol; [0499]
(1RS,2SR)-3-(methylamino)-1-(2-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0500]
(1RS,2SR)-1-(1H-benzimidazol-1-yl)-3-(methylamino)-1-phenylpropan--
2-ol; [0501]
(1RS,2SR)-3-(methylamino)-1-(2-methyl-1H-benzimidazol-1-yl)-1-phenylpropa-
n-2-ol; [0502]
(1RS,2SR)-1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol-
; [0503]
(1S,2R)-1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol; [0504]
(1S,2R)-1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0505]
(1S,2R)-1-(7-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol; [0506]
(1S,2R)-1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0507]
(1S,2R)-1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol; [0508]
(1RS,2SR)-1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol-
; [0509]
(1S,2R)-1-(3-fluorophenyl)-1-(6-methoxy-1H-indol-1-yl)-3-(methyla-
mino)propan-2-ol; [0510]
(1S,2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-1-yl)propan--
2-ol; [0511]
(1S,2R)-1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(meth-
ylamino)propan-2-ol; [0512]
(1S,2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-1-yl)propan--
2-ol; [0513]
(1S,2R)-1-(5-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol; [0514]
(1S,2R)-3-(methylamino)-1-(3-fluorophenyl)-1-(1H-pyrrolo[2,3-c]pyridin-1--
yl)propan-2-ol; [0515]
(1S,2R)-1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpr-
opan-2-ol; [0516]
(1S,2R)-3-(methylamino)-1-(6-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0517]
(1S,2R)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)-1-phenylpropan--
2-ol; [0518]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)prop-
an-2-ol; [0519]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)prop-
an-2-ol; [0520]
(1S,2R)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0521]
(1S,2R)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)-1-phenylpropan--
2-ol; [0522]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)prop-
an-2-ol; [0523]
(1S,2R)-1-(3-ethyl-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0524]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indol-1-yl)prop-
an-2-ol; [0525]
7-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one; [0526]
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dih-
ydro-2H-indol-2-one; [0527]
7-fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3-
,3-dimethyl-1,3-dihydro-2H-indol-2-one; [0528]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol;
[0529]
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol-
; [0530]
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cycloh-
exane-1,3'-indol]-2'(1'H)-one; [0531]
(1S,2R)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]etha-
nol; [0532]
(1R,2S)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]etha-
nol; [0533]
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclobutane-1,-
3'-indol]-2'(1'H)-one; [0534]
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclopentane-1-
,3'-indol]-2'(1'H)-one; [0535]
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclopropane-1-
,3'-indol]-2'(1'H)-one; [0536]
5-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one; [0537]
(1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-
-ol; [0538]
7'-fluoro-1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cycl-
ohexane-1,3'-indol]-2'(1'H)-one; [0539]
5'-bromo-1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-
hexane-1,3'-indol]-2'(1'H)-one; [0540]
(1S,2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol; [0541]
(1S,2R)-1-[3-(3,4-dichlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol; [0542]
(1S,2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol; [0543]
(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol; [0544]
(1S*,2R*)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol-
; [0545]
(1S,2R)-1-(5-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phe-
nylpropan-2-ol; [0546]
(1S,2R)-3-amino-1-(5-chloro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0547]
[(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpro-
pyl]methylamine; [0548]
(1S,2R)-1-(7-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol; [0549]
[(2R,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]met-
hylamine; [0550]
(1S,2R)-1-(4-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0551]
(1S,2R)-1-(4-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamin-
o)propan-2-ol; [0552]
(1S,2R)-1-(5-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0553]
(1S,2R)-1-(5-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamin-
o)propan-2-ol; [0554]
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-4-carbonit-
rile; [0555]
(1S,2R)-1-(6-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0556]
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-5-c-
arbonitrile; [0557]
1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1H-indole--
4-carbonitrile; [0558]
(1S,2R)-1-(6-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0559]
(1S,2R)-1-(6-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol; [0560]
(1S,2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol;
[0561]
(1S,2R)-1-(7-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol; [0562]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl)phenyl]pr-
opan-2-ol; [0563]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclohexane-1,3'-indol-
]-1 '(2'H)-ylpropan-2-ol; [0564]
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluorometh-
yl)phenyl]propan-2-ol; [0565]
(1S,2S)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol;
[0566]
(1S,2R)-1-(3,4-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)pr-
opan-2-ol; [0567]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)prop-
an-2-ol; [0568]
(1S,2R)-1-(4-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0569]
(1S,2R)-1-(6-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan--
2-ol; [0570]
(1S,2R)-1-(7-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0571]
(1S,2R)-1-(7-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylami-
no)propan-2-ol; [0572]
(1S,2R)-1-(4-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol; [0573]
(1S,2R)-1-(6-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol; [0574]
(1S,2R)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0575]
(1S,2R)-1-(5-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylami-
no)propan-2-ol; [0576]
(1S,2R)-1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol-
; [0577]
(1S,2R)-1-(3-fluorophenyl)-1-(3-isopropyl-1H-indol-1-yl)-3-(methy-
lamino)propan-2-ol; [0578]
(1S,2R)-1-(3,5-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2--
ol; [0579]
(1S,2R)-1-(3,5-difluorophenyl)-1-(2,3-dihydro-1H-indol-1-yl)-3--
(methylamino)propan-2-ol; [0580]
(1S,2R)-4-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)butan-2-ol;
[0581]
(1S,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(-
methylamino)propan-2-ol; [0582]
(1S,2R)-1-(3,5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
-3-(methylamino)propan-2-ol; [0583]
(1S,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phen-
ylpropan-2-ol; [0584]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol; [0585]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclopentane-1,3'-indo-
l]-1 '(2'H)-ylpropan-2-ol; [0586]
(1S,2R)-1-(3-fluorophenyl)-1-[3-(4-methoxyphenyl)-1H-indol-1-yl]-3-(methy-
lamino)propan-2-ol; [0587]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-methylphenyl)-1H-indol-
-1-yl]propan-2-ol; [0588]
(1S,2R)-1-[3-(4-tert-butylphenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol; [0589]
(1S,2R)-1-(3-fluorophenyl)-1-[3-(3-methoxyphenyl)-1H-indol-1-yl]-3-(methy-
lamino)propan-2-ol; [0590]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl)pheny-
l]-1H-indol-1-yl}propan-2-ol; [0591]
(1S,2R)-1-(3,5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-3-(-
methylamino)propan-2-ol; [0592]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl)pheny-
l]-1H-indol-1-yl}propan-2-ol; [0593]
(1S,2R)-1-(3-fluorophenyl)-1-[3-(2-methoxyphenyl)-1H-indol-1-yl]-3-(methy-
lamino)propan-2-ol; [0594]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl)pheny-
l]-1H-indol-1-yl}propan-2-ol; [0595]
(1S,2R)-3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0596]
(1S,2R)-1-(7-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol; [0597]
(1S,2R)-3-amino-1-(7-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol;
[0598]
(1S,2R)-1-(7-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan--
2-ol; [0599]
(1S,2R)-1-(4-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol;
[0600]
(1S,2R)-1-(7-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylami-
no)propan-2-ol; [0601]
(1S,2R)-1-(4-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol; [0602]
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indo-
l-1-yl]propan-2-ol;
[0603]
(1S,2R)-1-(6-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan--
2-ol; [0604]
(1S,2R)-3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indol-1-yl]pro-
pan-2-ol; [0605]
(1S,2R)-3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indol-1-yl]pro-
pan-2-ol; [0606]
(1S,2R)-1-(3-tert-butyl-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)-
propan-2-ol; [0607]
(1S,2R)-1-(1H-indol-1-yl)-2-methyl-3-(methylamino)-1-phenylpropan-2-ol;
[0608]
(2R,3S)-3-(1H-indol-1-yl)-1-(methylamino)-3-phenylbutan-2-ol;
[0609]
1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]--
1,3-dihydro-2H-benzimidazol-2-one; [0610]
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-propyl-1,3-dihydro-
-2H-benzimidazol-2-one; [0611]
5-bromo-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-
-1,3-dihydro-2H-indol-2-one; [0612]
6-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one; [0613]
4-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one; [0614]
1-cyclobutyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dih-
ydro-2H-benzimidazol-2-one; [0615]
5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1-propyl-1,-
3-dihydro-2H-benzimidazol-2-one; [0616]
1-ethyl-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1,-
3-dihydro-2H-benzimidazol-2-one; [0617]
1-ethyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro--
2H-benzimidazol-2-one; [0618]
4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1-isopropyl-
-1,3-dihydro-2H-benzimidazol-2-one; [0619]
1-cyclopentyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-di-
hydro-2H-benzimidazol-2-one; [0620]
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-isopropyl-1,3-dihy-
dro-2H-benzimidazol-2-one; [0621]
3-[(1S,2R)-3-(ethylamino)-2-hydroxy-1-phenylpropyl]-5-fluoro-1-isopropyl--
1,3-dihydro-2H-benzimidazol-2-one; [0622]
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-methyl-1,3-dihydro-
-2H-benzimidazol-2-one; [0623]
1-ethyl-5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-
-dihydro-2H-benzimidazol-2-one; [0624]
1-ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-
-dihydro-2H-benzimidazol-2-one; [0625]
4-fluoro-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1-
-isopropyl-1,3-dihydro-2H-benzimidazol-2-one; [0626]
1-ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-(3-fluorophenyl)--
propyl]-1,3-dihydro-2H-benzimidazol-2-one; [0627]
1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimeth-
yl-1,3-dihydro-2H-indol-2-one; [0628]
(1S,2R)-1-[3-(2,3-difluorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol; [0629]
(1S,2R)-1-[3-(2-chlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methyl-
amino)propan-2-ol; and
[0630] pharmaceutically acceptable salts thereof, particularly
hydrochloride and dihydrochloride salts thereof.
[0631] Some of the compounds of the present invention may contain
chiral centers and such compounds may exist in the form of
stereoisomers (i.e. enantiomers). The present invention includes
all such stereoisomers and any mixtures thereof including racemic
mixtures. Racemic mixtures of the stereoisomers as well as the
substantially pure stereoisomers are within the scope of the
invention. The term "substantially pure," as used herein, refers to
at least about 90 mole %, more preferably at least about 95 mole %,
and most preferably at least about 98 mole % of the desired
stereoisomer is present relative to other possible stereoisomers.
Preferred enantiomers may be isolated from racemic mixtures by any
method known to those skilled in the art, including high
performance liquid chromatography (HPLC) and the formation and
crystallization of chiral salts or prepared by methods described
herein. See, for example, Jacques, et al., Enantiomers, Racemates
and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H.,
et al., Tetrahedron, 33:2725 (1977); Eliel, E.L. Stereochemistry of
Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of
Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed.,
University of Notre Dame Press, Notre Dame, Ind. 1972).
[0632] The present invention includes prodrugs of the compounds of
formula I. "Prodrug," as used herein, means a compound which is
convertible in vivo by metabolic means (e.g. by hydrolysis) to a
compound of formula I. Various forms of prodrugs are known in the
art, for example, as discussed in Bundgaard, (ed.), Design of
Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in
Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et
al., (ed). "Design and Application of Prodrugs," Textbook of Drug
Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et
al., Journal of Drug Deliver Reviews, 1992, 8:1-38, Bundgaard, J.
of Pharmaceutical Sciences, 1988, 77:285 et seq.; and Higuchi and
Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American
Chemical Society (1975).
[0633] Further, the compounds of formula I may exist in unsolvated
as well as in solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, the like. In general, the solvated
forms are considered equivalent to the unsolvated forms for the
purpose of the present invention.
[0634] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art. The
compounds can be synthesized, for example, by the methods described
below, or variations thereon as appreciated by the skilled artisan.
All processes disclosed in association with the present invention
are contemplated to be practiced on any scale, including milligram,
gram, multigram, kilogram, multikilogram or commercial industrial
scale.
[0635] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Protecting groups that may be
employed in accordance with the present invention may be described
in Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic
Synthesis 2d. Ed., Wiley & Sons, 1991.
[0636] Compounds of the present invention are suitably prepared in
accordance with the following general description and specific
examples. Variables used are as defined for formula I, unless
otherwise noted. The reagents used in the preparation of the
compounds of this invention can be either commercially obtained or
can be prepared by standard procedures described in the literature.
In accordance with this invention, compounds of formula I are
produced by the following reaction schemes (Scheme I-IV).
[0637] The compounds of this invention contain chiral centers,
proving for various stereoisomeric forms such as enantiomeric
mixtures as well as optical isomers. The individual optical isomers
can be prepared directly through asymmetric and/or stereospecific
synthesis or by conventional chiral separation of optical isomers
from the enantiomeric mixture.
[0638] Compounds of the present invention are suitably prepared in
accordance with the following general description and specific
examples. Variables used are as defined for formula I, unless
otherwise noted. The reagents used in the preparation of the
compounds of this invention can be either commercially obtained or
can be prepared by standard procedures described in the literature.
In accordance with this invention, compounds of formula I are
produced by the following reaction schemes (Scheme I-IV).
[0639] The compounds of this invention contain chiral centers,
providing various stereoisomeric forms such as enantiomeric
mixtures as well as optical isomers. The individual optical isomers
can be prepared directly through asymmetric and/or stereospecific
synthesis or by conventional chiral separation of optical isomers
from the enantiomeric mixture.
[0640] In accordance with this invention, compounds of formula I
are produced by the following reaction schemes (Schemes I to IV).
Depending on the desired diastereomer, the compounds can be
prepared via two different synthetic routes (A and B, Schemes I and
II). If it is desired to synthesize compounds of formula I-a, they
can be prepared from compounds of formula 4 by selectively
converting the primary alcohol into a leaving group and displacing
it with a desired amine. (Route A, Scheme I) Any conventional
method for the selective conversion of a primary alcohol into a
leaving group, and any conventional method for displacing a primary
leaving group with an amine can be utilized for this conversion. In
accordance with the preferred embodiment of this invention, the
diol of formula 4 is treated with para-toluenesulfonyl chloride in
pyridine to form the tosylate of formula 5, which is converted to
the compound of formula I-a through treatment with an excess of
alcoholic amine solution, either at room temperature or heated to
about 40.degree. C. to about 80.degree. C. in a sealed tube.
Compounds of formula I-a can be converted to a pharmaceutically
acceptable salt using any conventional method.
##STR00004##
[0641] If it is desired to form compounds of formula I-aa, they can
be prepared from compounds of formula 4 via selective protection of
the primary alcohol, followed by alkylation of the secondary
alcohol, and deprotection of the primary alcohol. Any conventional
alcohol protecting groups can be utilized for this conversion and
any method for the selective protection of a primary alcohol can be
employed. According to the preferred embodiment of this invention,
the reaction is carried out at low temperature in dichloromethane
with trimethylsilyl chloride and triethylamine as base to form
compounds of formula 6. Alkylation of the secondary alcohol can be
accomplished via any conventional method of alkylating a secondary
alcohol found in the literature. According to the preferred
embodiment of this invention, compounds of formula 6 are reacted
with an alkyl halide using sodium hydride as base to form compounds
of formula 8, which can be deprotected to form compounds of formula
9 via any conventional method for deprotection of a primary
alcohol. According to the preferred embodiment of this invention,
compounds of formula 8 are treated with dilute aqueous hydrochloric
acid or trifluoroacetic acid in dichloromethane to form compounds
of formula 9. Conversion of the primary alcohol in compounds of
formula 9 to complete the synthesis of compounds of formula I-aa
can be performed as previously described for the synthesis of
compounds of formula I-a. Compounds of formula I-aa can be
converted to a pharmaceutically acceptable salt using any
conventional method.
[0642] Alternatively, compounds of formula 10 can be prepared
directly from compounds of formula 5. Any method of alkylating a
hydroxyl group in the presence of a tosyl group can be employed for
this conversion. In accordance with the preferred embodiment of
this invention, compounds of formula 5 are treated with an alkyl
trifluoromethanesulfonate, e.g. methyl trifluoromethanesulfonate,
in the presence of a hindered base, e.g.
2,6-di-tert-butyl-4-methylpyridine. The reaction can be performed
either at room temperature or heated to about 40.degree. C. to
about 80.degree. C. Compounds of formula 10 can be converted to
compounds of formula I-aa as previously described for the synthesis
of compounds of formula I-a. Compounds of formula I-aa can be
converted to a pharmaceutically acceptable salt using any
conventional method.
[0643] If it is desired to form compounds of I-b, they can also be
prepared from compounds of formula 4 via Route B (Scheme II). This
route involves the selective protection of the primary alcohol
followed by conversion of the secondary alcohol to a leaving group.
Any conventional method for the selective protection of a primary
alcohol, and any conventional method for converting of a secondary
alcohol into a leaving group can be utilized for this conversion.
In accordance with the preferred embodiment of this invention,
compounds of formula 4 are treated with para-nitrobenzoyl chloride
in pyridine at low temperature (preferably below about 0.degree.
C.) to form compounds of formula 11. Compounds of formula 11 can be
converted to a secondary mesylate of formula 12 via reaction with
methanesulfonyl chloride in dichloromethane using triethylamine as
base. The reaction is preferably carried out at temperatures
between about -15.degree. C. and about 10.degree. C. Deprotection
of the primary alcohol in compounds of formula 12 allows for the
formation of a primary epoxide through an S.sub.N2 reaction
resulting in an inversion of the stereocenter. Any conventional
method for deprotection of a primary alcohol, and any conventional
method for epoxide formation onto an alpha leaving group can be
employed for this conversion. In accordance with the preferred
embodiment of this invention, compounds of formula 12 are treated
with an aqueous solution of a suitable base in organic solvent,
preferably, aqueous sodium hydroxide in dioxane. The resulting
epoxide of formula 13 can be ring-opened regioselectively with an
amine to produce the desired aminoalcohol of formula I-b. Any
conventional method for the regioselective ring opening of a
primary epoxide can be employed for this conversion. In accordance
with the preferred embodiment of this invention, compounds of
formula 13 are treated with an excess of an alcoholic amine
solution in a sealed flask, either at room temperature or heated to
about 40.degree. C. to about 90.degree. C. Compounds of formula I-b
can be converted into a pharmaceutically acceptable salt using
conventional methods.
##STR00005##
[0644] If it is desired to form compounds of formula I-bb, they can
be made from compounds of formula I-b via protection of the amine,
alkylation of the secondary alcohol and deprotection of the amine
(Scheme III). Any conventional method for protection of an amine,
alkylation of a secondary alcohol, and deprotection of an amine can
be utilized for this conversion. In accordance with the preferred
embodiment of this invention, compounds of formula I-b are treated
with boc anhydride, where boc=tert-butoxycarbonyl, to form
compounds of formula 14 which can be alkylated with an alkyl halide
using sodium hydride as base to form compounds of formula 15.
Deprotection is accomplished using an acid, preferably
trifluoroacetic acid in dichloromethane to form compounds of
formula I-bb that can be converted into a pharmaceutically
acceptable salt using conventional methods.
##STR00006##
[0645] Compounds of formula 4 are formed via a regio- and
stereo-selective ring opening of an appropriately substituted
epoxide of formula 17 (formed via an epoxidation of an
appropriately substituted allylic alcohol) with an appropriately
substituted compound of formula 16 (Scheme IV). Any conventional
method for the regio- and stereo-selective ring opening of an
epoxide can be employed for this conversion. In accordance with the
preferred embodiment of this invention, compounds of formula 16 are
treated with a base, e.g. sodium hydride, sodium tert-butoxide,
potassium hydroxide, potassium tert-butoxide or potassium
hydroxide, then treated with the epoxide of formula 17. The epoxide
of formula 17 can be pre-treated with a Lewis acid, e.g. titanium
iso-propoxide, boron-trifluoride, etc. to ensure regio-selective
ring-opening. The reaction occurs at room temperature over a
duration of about 2 hours to about 72 hours. Alternatively,
compounds of formula 16 that are suitably nucleophilic, e.g.
indoline, can be heated with the epoxide of formula 17 at
temperatures from about 50.degree. C. to about 170.degree. C. to
form compounds of formula 4.
[0646] Epoxidation of trans-allylic alcohols can be performed
either racemically or asymmetrically using methods described in the
literature. In accordance with the preferred embodiment of this
invention, racemic epoxidation is conducted with either peracetic
acid or meta-chloroperbenzoic acid. If it is desired to produce a
single enantiomer of compounds of formula I, asymmetric epoxidation
of an allylic alcohol can be performed with tert-butylhydroperoxide
or cumene hydroperoxide in the presence of the appropriate tartrate
ester, titanium (IV) isopropoxide, and molecular sieves. This
method is well established in the literature (e.g. K. B. Sharpless,
et. al., J. Org. Chem. 1986, 51, 3710). Compounds of formula 16 and
the starting allylic alcohols are either available from commercial
sources or are accessible through methods well established in the
literature.
##STR00007##
[0647] In other embodiments, the invention is directed to
pharmaceutical compositions, comprising:
a. at least compound of formula I, or pharmaceutically acceptable
salt thereof;
[0648] and
b. at least one pharmaceutically acceptable carrier. Generally, the
compound of formula I, or a pharmaceutically acceptable salt
thereof, will be present at a level of from about 0.1%, by weight,
to about 90% by weight, based on the total weight of the
pharmaceutical composition, based on the total weight of the
pharmaceutical composition. Preferably, the compound of formula I,
or a pharmaceutically acceptable salt thereof, will be present at a
level of at least about 1%, by weight, based on the total weight of
the pharmaceutical composition. More preferably, the compound of
formula I, or a pharmaceutically acceptable salt thereof, will be
present at a level of at least about 5%, by weight, based on the
total weight of the pharmaceutical composition. Even more
preferably, the norepinephrine reuptake inhibitor or a
pharmaceutically acceptable salt thereof will be present at a level
of at least about 10%, by weight, based on the total weight of the
pharmaceutical composition. Yet even more preferably, the compound
of formula I, or a pharmaceutically acceptable salt thereof, will
be present at a level of at least about 25%, by weight, based on
the total weight of the pharmaceutical composition.
[0649] Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's
Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro,
Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically
acceptable carriers are those that are compatible with the other
ingredients in the formulation and biologically acceptable.
[0650] The compounds of this invention may be administered orally
or parenterally, neat or in combination with conventional
pharmaceutical carriers. Applicable solid carriers can include one
or more substances that may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or an
encapsulating material. In powders, the carrier is a finely divided
solid that is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to 99% of the active
ingredient. Suitable solid carriers include, for example, calcium
phosphate, magnesium stearate, talc, sugars, lactose, dextrin,
starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl
cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange
resins.
[0651] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups, and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers, or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
[0652] Liquid pharmaceutical compositions, which are sterile
solutions or suspensions, can be administered by, for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. Oral
administration may be either liquid or solid composition form.
[0653] Preferably the pharmaceutical composition is in unit dosage
form, e.g. as tablets, capsules, powders, solutions, suspensions,
emulsions, granules, or suppositories. In such form, the
composition is sub-divided in unit dose containing appropriate
quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example packeted powders, vials,
ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself,
or it can be the appropriate number of any such compositions in
package form.
[0654] In another embodiment of the present invention, the
compounds useful in the present invention may be administered to a
mammal with one or more other pharmaceutical active agents such as
those agents being used to treat any other medical condition
present in the mammal. Examples of such pharmaceutical active
agents include pain relieving agents, anti-angiogenic agents,
anti-neoplastic agents, anti-diabetic agents, anti-infective
agents, or gastrointestinal agents, or combinations thereof.
[0655] The one or more other pharmaceutical active agents may be
administered in a therapeutically effective amount simultaneously
(such as individually at the same time, or together in a
pharmaceutical composition), and/or successively with one or more
compounds of the present invention.
[0656] The term "combination therapy" refers to the administration
of two or more therapeutic agents or compounds to treat a
therapeutic condition or disorder described in the present
disclosure, for example hot flush, sweating,
thermoregulatory-related condition or disorder, or other. Such
administration includes use of each type of therapeutic agent in a
concurrent manner. In either case, the treatment regimen will
provide beneficial effects of the drug combination in treating the
conditions or disorders described herein.
[0657] The route of administration may be any route, which
effectively transports the active compound of formula I, or a
pharmaceutically acceptable salt thereof, to the appropriate or
desired site of action, such as oral, nasal, pulmonary,
transdermal, such as passive or iontophoretic delivery, or
parenteral, e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intranasal, ophthalmic solution or an
ointment. Furthermore, the administration of compound of formula I,
or pharmaceutically acceptable salt thereof, with other active
ingredients may be concurrent or simultaneous.
[0658] It is believed that the present invention described presents
a substantial breakthrough in the field of treatment, alleviation,
inhibition, and/or prevention of conditions ameliorated by
monoamine reuptake including, inter alia, vasomotor symptoms (VMS),
sexual dysfunction, gastrointestinal and genitourinary disorders,
chronic fatigue syndrome, fibromylagia syndrome, nervous system
disorders, and combinations thereof, particularly those conditions
selected from the group consisting of major depressive disorder,
vasomotor symptoms, stress and urge urinary incontinence,
fibromyalgia, pain, diabetic neuropathy, and combinations
thereof.
[0659] Accordingly, in one embodiment, the present invention is
directed to methods for treating or preventing a condition
ameliorated by monoamine reuptake in a subject in need thereof,
comprising the step of:
[0660] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0661] The conditions ameliorated by monoamine reuptake include
those selected from the group consisting of vasomotor symptoms,
sexual dysfunction, gastrointestinal and genitourinary disorders,
chronic fatigue syndrome, fibromylagia syndrome, nervous system
disorders, and combinations thereof, particularly those conditions
selected from the group consisting of major depressive disorder,
vasomotor symptoms, stress and urge urinary incontinence,
fibromyalgia, pain, diabetic neuropathy, and combinations
thereof.
[0662] "Vasomotor symptoms," "vasomotor instability symptoms" and
"vasomotor disturbances" include, but are not limited to, hot
flushes (flashes), insomnia, sleep disturbances, mood disorders,
irritability, excessive perspiration, night sweats, fatigue, and
the like, caused by, inter alia, thermoregulatory dysfunction.
[0663] The term "hot flush" is an art-recognized term that refers
to an episodic disturbance in body temperature typically consisting
of a sudden skin flushing, usually accompanied by perspiration in a
subject.
[0664] The term "sexual dysfunction" includes, but is not limited
to, condition relating to desire and/or arousal.
[0665] As used herein, "gastrointestinal and genitourinary
disorders" includes irritable bowel syndrome, symptomatic GERD,
hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest
pain, biliary dyskinesia, sphincter of Oddi dysfunction,
incontinence (i.e., urge incontinence, stress incontinence, genuine
stress incontinence, and mixed incontinence)(including the
involuntary voiding of feces or urine, and dribbling or leakage or
feces or urine which may be due to one or more causes including but
not limited to pathology altering sphincter control, loss of
cognitive function, overdistention of the bladder, hyperreflexia
and/or involuntary urethral relaxation, weakness of the muscles
associated with the bladder or neurologic abnormalities),
interstitial cystitis (irritable bladder), and chronic pelvic pain
(including, but not limited to vulvodynia, prostatodynia, and
proctalgia).
[0666] As used herein, "chronic fatigue syndrome" (CFS) is a
condition characterized by physiological symptoms selected from
weakness, muscle aches and pains, excessive sleep, malaise, fever,
sore throat, tender lymph nodes, impaired memory and/or mental
concentration, insomnia, disordered sleep, localized tenderness,
diffuse pain and fatigue, and combinations thereof.
[0667] As used herein, "fibromyalgia syndrome" (FMS) includes FMS
and other somatoform disorders, including FMS associated with
depression, somatization disorder, conversion disorder, pain
disorder, hypochondriasis, body dysmorphic disorder,
undifferentiated somatoform disorder, and somatoform NOS. FMS and
other somatoform disorders are accompanied by physiological
symptoms selected from a generalized heightened perception of
sensory stimuli, abnormalities in pain perception in the form of
allodynia (pain with innocuous stimulation), abnormalities in pain
perception in the form of hyperalgesia (increased sensitivity to
painful stimuli), and combinations thereof.
[0668] As used herein, "nervous system disorders," includes
addictive disorders (including those due to alcohol, nicotine, and
other psychoactive substances) and withdrawal syndrome,
age-associated learning and mental disorders (including Alzheimer's
disease), anorexia nervosa, bulimia nervosa, attention-deficit
disorder with or without hyperactivity disorder bipolar disorder,
pain, cyclothymic disorder, depression disorder (including major
depressive disorder, refractory depression adolescent depression
and minor depression), dysthymic disorder, generalized anxiety
disorder (GAD), obesity (i.e., reducing the weight of obese or
overweight patients), obsessive compulsive disorders and related
spectrum disorders, oppositional defiant disorder, panic disorder,
post-traumatic stress disorder, premenstrual dysphoric disorder
(i.e., premenstrual syndrome and late luteal phase dysphoric
disorder), psychotic disorders (including schizophrenia,
schizoaffective and schizophreniform disorders), seasonal affective
disorder, sleep disorders (such as narcolepsy and enuresis), social
phobia (including social anxiety disorder), selective serotonin
reuptake inhibition (SSRI) "poop out" syndrome (i.e., wherein a
patient who fails to maintain a satisfactory response to SSRI
therapy after an initial period of satisfactory response).
[0669] As used herein, "pain," includes both acute pain and chronic
pain, which may be centralized pain, peripheral pain, or
combination thereof. The term includes many different types of
pains including, but not limited to, neuropathic pain, visceral
pain, musculoskeletal pain, bony pain, cancer pain, inflammatory
pain, and combinations thereof, such as lower back pain, atypical
chest pain, headache such as cluster headache, migraine, herpes
neuralgia, phantom limb pain, pelvic pain, myofascial face pain,
abdominal pain, neck pain, central pain, dental pain, opioid
resistant pain, visceral pain, surgical pain, bone injury pain,
pain during labor and delivery, pain resulting from burns, post
partum pain, angina pain, neuropathic pain such as peripheral
neuropathy and diabetic neuropathy, post-operative pain, and pain
which is co-morbid with nervous system disorders described
herein.
[0670] As used herein, the term "acute pain" refers to centralized
or peripheral pain that is intense, localized, sharp, or stinging,
and/or dull, aching, diffuse, or burning in nature and that occurs
for short periods of time.
[0671] As used herein, the term "chronic pain" refers to
centralized or peripheral pain that is intense, localized, sharp,
or stinging, and/or dull, aching, diffuse, or burning in nature and
that occurs for extended periods of time (i.e., persistent and/or
regularly reoccurring), including, for the purpose of the present
invention, neuropathic pain and cancer pain. Chronic pain includes
neuropathic pain, hyperalgesia, and/or allodynia.
[0672] As used herein, the term "neuropathic pain" refers to
chronic pain caused by damage to or pathological changes in the
peripheral or central nervous systems. Examples of pathological
changes related to neuropathic pain include prolonged peripheral or
central neuronal sensitization, central sensitization related
damage to nervous system inhibitory and/or exhibitory functions and
abnormal interactions between the parasympathetic and sympathetic
nervous systems. A wide range of clinical conditions may be
associated with or form the basis for neuropathic pain including,
for example, diabetes, post traumatic pain of amputation (nerve
damage cause by injury resulting in peripheral and/or central
sensitization such as phantom limb pain), lower back pain, cancer,
chemical injury, toxins, other major surgeries, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, or viral or bacterial infections such as
shingles or human immunodeficiency virus (HIV), and combinations
thereof. Also included in the definition of neuropathic pain is a
condition secondary to metastatic infiltration, adiposis dolorosa,
burns, central pain conditions related to thalamic conditions, and
combinations thereof.
[0673] As used herein, the term "hyperalgesia" refers to pain where
there is an increase in sensitivity to a typically noxious
stimulus.
[0674] As used herein, the term "allodynia" refers to an increase
in sensitivity to a typically non-noxious stimulus.
[0675] As used herein, the term "visceral pain" refers to pain
associated with or resulting from maladies of the internal organs,
such as, for example, ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, and combinations thereof.
[0676] As used herein, the term "female-specific pain" refers to
pain that may be acute and/or chronic pain associated with female
conditions. Such groups of pain include those that are encountered
solely or predominately by females, including pain associated with
menstruation, ovulation, pregnancy or childbirth, miscarriage,
ectopic pregnancy, retrograde menstruation, rupture of a follicular
or corpus luteum cyst, irritation of the pelvic viscera, uterine
fibroids, adenomyosis, endometriosis, infection and inflammation,
pelvic organ ischemia, obstruction, intra-abdominal adhesions,
anatomic distortion of the pelvic viscera, ovarian abscess, loss of
pelvic support, tumors, pelvic congestion or referred pain from
non-gynecological causes, and combinations thereof.
[0677] In one embodiment, the present invention is directed to
methods for treating or preventing vasomotor symptoms in a subject
in need thereof, comprising the step of:
[0678] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0679] When estrogen levels are low or estrogen is absent, the
normal levels between NE and 5-HT is altered and this altered
change in neurotransmitter levels may result in changes in the
sensitivity of the thermoregulatory center. The altered chemical
levels may be translated in the thermoregulatory center as heat
sensation and as a response, the hypothalamus may activate the
descending autonomic pathways and result in heat dissipation via
vasodilation and sweating (hot flush) (FIG. 1). Accordingly, the
estrogen deprivation may result in altered norepinephrine
activity.
[0680] Norepinephrine synthesized in perikarya of the brainstem is
released at the nerve terminals in the hypothalamus and brainstem.
In the hypothalamus, NE regulates the activity of neurons residing
in the thermoregulatory center. In the brainstem, NE innervates
serotoninergic neurons (5HT), and acting via
adrenergic.sub..alpha.1 and adrenergic.sub..alpha.2 postsynaptic
receptors, it stimulates the activity of the serotoninergic system.
In response, 5-HT neurons also modulate the activity the
thermoregulatory center and feedback to NE neurons. Via this
feedback connection, 5-HT, acting via 5-HT.sub.2a receptors,
inhibit the activity of NE neurons. Norepinephrine in the synaptic
cleft is also taken up by NE transporter (NET) located in NE
neurons. The transporter recycles NE and makes it available for
multiple neurotransmission (FIG. 2).
[0681] The present invention provides a treatment for vasomotor
symptoms by methods of recovering the reduced activity of
norepinephrine. Norepinephrine activity in the hypothalamus or in
the brainstem can be elevated by (i) blocking the activity of the
NE transporter, (ii) blocking the activity of the presynaptic
adrenergic.sub..alpha.2 receptor with an antagonist, or (iii)
blocking the activity of 5-HT on NE neurons with a 5-HT.sub.2a
antagonist.
[0682] In another embodiment, the present invention is directed to
methods for treating or preventing a depression disorder in a
subject in need thereof, comprising the step of:
[0683] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0684] In yet other embodiments, the present invention is directed
to methods for treating or preventing sexual dysfunction in a
subject in need thereof, comprising the step of:
[0685] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0686] In another embodiment, the present invention is directed to
methods for treating or preventing gastrointestinal or
genitourinary disorder, particularly stress incontinence or urge
urinary incontinence, in a subject in need thereof, comprising the
step of:
[0687] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0688] In another embodiment, the present invention is directed to
methods for treating or preventing chronic fatigue syndrome in a
subject in need thereof, comprising the step of:
[0689] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0690] In another embodiment, the present invention is directed to
methods for treating or preventing fibromylagia syndrome in a
subject in need thereof, comprising the step of:
[0691] administering to said subject an effective amount of a
compound of formula I or pharmaceutically acceptable salt
thereof.
[0692] In further embodiments, the present invention is directed to
methods for treating or preventing pain in a subject in need
thereof, comprising the step of:
[0693] administering to said subject an effective amount of at
least one compound of formula I or pharmaceutically acceptable salt
thereof.
[0694] The pain may be, for example, acute pain (short duration) or
chronic pain (regularly reoccurring or persistent). The pain may
also be centralized or peripheral.
[0695] Examples of pain that can be acute or chronic and that can
be treated in accordance with the methods of the present invention
include inflammatory pain, musculoskeletal pain, bony pain,
lumbosacral pain, neck or upper back pain, visceral pain, somatic
pain, neuropathic pain, cancer pain, pain caused by injury or
surgery such as burn pain or dental pain, or headaches such as
migraines or tension headaches, or combinations of these pains. One
skilled in the art will recognize that these pains may overlap one
another. For example, a pain caused by inflammation may also be
visceral or musculoskeletal in nature.
[0696] In a preferred embodiment of the present invention the
compounds useful in the present invention are administered in
mammals to treat chronic pain such as neuropathic pain associated
for example with damage to or pathological changes in the
peripheral or central nervous systems; cancer pain; visceral pain
associated with for example the abdominal, pelvic, and/or perineal
regions or pancreatitis; musculoskeletal pain associated with for
example the lower or upper back, spine, fibromylagia,
temporomandibular joint, or myofascial pain syndrome; bony pain
associated with for example bone or joint degenerating disorders
such as osteoarthritis, rheumatoid arthritis, or spinal stenosis;
headaches such migraine or tension headaches; or pain associated
with infections such as HIV, sickle cell anemia, autoimmune
disorders, multiple sclerosis, or inflammation such as
osteoarthritis or rheumatoid arthritis.
[0697] In a more preferred embodiment, the compounds useful in this
invention are used to treat chronic pain that is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain or
inflammatory pain or combinations thereof, in accordance with the
methods described herein. Inflammatory pain can be associated with
a variety of medical conditions such as osteoarthritis, rheumatoid
arthritis, surgery, or injury. Neuropathic pain may be associated
with for example diabetic neuropathy, peripheral neuropathy,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, or nerve damage cause by injury resulting in peripheral
and/or central sensitization such as phantom limb pain, reflex
sympathetic dystrophy or postthoracotomy pain, cancer, chemical
injury, toxins, nutritional deficiencies, or viral or bacterial
infections such as shingles or HIV, or combinations thereof. The
methods of use for compounds of this invention further include
treatments in which the neuropathic pain is a condition secondary
to metastatic infiltration, adiposis dolorosa, burns, or central
pain conditions related to thalamic conditions.
[0698] As mentioned previously, the methods of the present
invention may be used to treat pain that is somatic and/or visceral
in nature. For example, somatic pain that can be treated in
accordance with the methods of the present invention include pains
associated with structural or soft tissue injury experienced during
surgery, dental procedures, burns, or traumatic body injuries.
Examples of visceral pain that can be treated in accordance with
the methods of the present invention include those types of pain
associated with or resulting from maladies of the internal organs
such as ulcerative colitis, irritable bowel syndrome, irritable
bladder, Crohn's disease, rheumatologic (arthralgias), tumors,
gastritis, pancreatitis, infections of the organs, or biliary tract
disorders, or combinations thereof. One skilled in the art will
also recognize that the pain treated according to the methods of
the present invention may also be related to conditions of
hyperalgesia, allodynia, or both. Additionally, the chronic pain
may be with or without peripheral or central sensitization.
[0699] The compounds useful in this invention may also be used to
treat acute and/or chronic pains associated with female conditions,
which may also be referred to as female-specific pain. Such groups
of pain include those that are encountered solely or predominately
by females, including pain associated with menstruation, ovulation,
pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde
menstruation, rupture of a follicular or corpus luteum cyst,
irritation of the pelvic viscera, uterine fibroids, adenomyosis,
endometriosis, infection and inflammation, pelvic organ ischemia,
obstruction, intra-abdominal adhesions, anatomic distortion of the
pelvic viscera, ovarian abscess, loss of pelvic support, tumors,
pelvic congestion or referred pain from non-gynecological
causes.
[0700] The present invention is further defined in the following
Examples, in which all parts and percentages are by weight and
degrees are Celsius, unless otherwise stated. It should be
understood that these examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only. From the above discussion and these examples, one skilled in
the art can ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions.
EXAMPLES
Example 1
(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl
propan-2-ol Dihydrochloride
##STR00008##
[0702] Step 1: A mixture of indole (2.34 g, 20 mmol) and pulverized
solid potassium hydroxide (1.12 g, 20 mmol) was stirred for 30
minutes under nitrogen at room temperature. Trans-3-phenylglycidol
(3.0 g, 20 mmol) in dimethylsulfoxide (1 mL) was then added and the
mixture was stirred at 70.degree. C. for 2 hours until no epoxide
remained. The mixture was then cooled and partitioned between water
and dichloromethane. The organic layer was separated, washed with
water several times, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was purified via
Biotage chromatography (FlasH40i, silica, 10%, 20%, 30% ethyl
acetate/hexane) to yield 1.92 g (36%) of
(2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol as an oil.
.sup.1HNMR (DMSO): .delta. 3.27 (m, 2H, CH.sub.2OH), .delta. 4.45
(m, 1H, CHOH), .delta. 4.80 (t, 1H, CH.sub.2OH), .delta. 5.20 (d,
1H, CHOH), .delta. 5.60 (d, 1H, CHPh); MS (ESI) m/z 268
([M+H].sup.+).
[0703] Step 2: A solution of
(2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol (1.83 g, 6.8 mmol)
and p-toluenesulfonyl chloride (1.31 g, 6.8 mmol) in anhydrous
pyridine (10 mL) was stirred at room temperature under nitrogen for
15 hours. The mixture was then diluted with water (10 mL), quenched
with a 2N aqueous solution of hydrochloric acid in an ice/water
bath until the solution was pH=3, and extracted with
dichloromethane. The organic layer was washed with water again,
dried over anhydrous sodium sulfate, filtered, and concentrated.
The residue was purified via Biotage chromatography (FlasH40i,
silica, 10%, 25% EtOAc/hexane) to yield 1.98 g (69%) of (2RS,3
RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl
ester as a white solid. .sup.1HNMR (DMSO): .delta. 3.70 and .delta.
3.85 (dd and dd, 2H, CH.sub.2OTs), .delta. 4.80 (m, 1H, CHOH),
.delta. 5.52 (d, 1H, CHPh), .delta. 5.82 (d, 1H, CHOH); MS (ESI)
m/z 422 ([M+H].sup.+).
[0704] Step 3: A mixture of (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (0.185 g, 0.4 mmol),
1-methyl piperazine (0.05 mL, 0.4 mmol) and potassium carbonate
(0.07 g, 0.44 mmol) in acetonitrile (10 mL) was stirred at reflux
under nitrogen for 24 hours. After cooling, the mixture was
filtered and the filtrate was concentrated and purified via Biotage
chromatography (5% methanol/dichloromethane) to give a white solid
of
(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-o-
l. The free base was dissolved in a minimum amount of ethanol and
treated with a 1N ethereal solution of hydrochloric acid until the
solution was pH=3 followed by diethyl ether. The product was then
crystallized by adding a minimum amount of hexane to afford the
titled compound,
(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-o-
l dihydrochloride as an off-white solid. MS m/z 350 ([M+H].sup.+);
HRMS: calcd for C.sub.22H.sub.27N.sub.3O+H+, 350.22269; found (ESI,
[M+H]+), 350.2228.
Example 2
(1RS,2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpr-
opan-2-ol Dihydrochloride
##STR00009##
[0706] In an analogous manner to EXAMPLE 1, step 1
(2RS,3RS)-3-(5-fluoro-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 5-fluoroindole and trans-3-phenylglycidol as an oil.
MS (ESI) m/z 286 ([M+H].sup.+).
[0707] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(5-fluoro-indol-1-yl)-3-phenyl-propane-1,2-diol. MS
(ESI) m/z 440 ([M+H].sup.+).
[0708] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylp-
ropan-2-ol dihydrochloride was prepared from
(2RS,3RS)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. MS m/z 368
([M+H].sup.+); HRMS: calcd for C.sub.22H.sub.26FN.sub.3O+H+,
368.21327; found (ESI, [M+H]+), 368.213.
Example 3
(1RS,2SR)-1-(1H-indol-1-yl)-3-morpholin-4-yl-1-phenylpropan-2-ol
Hydrochloride
##STR00010##
[0710] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-o-
l hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3)
and morpholine. MS (ESI) m/z 337 ([M+H].sup.+); HRMS: calcd for
C.sub.21H.sub.24N.sub.2O.sub.2+H+, 337.19105; found (ESI, [M+H]+),
337.1909.
Example 4
(1RS,2SR)-3-(dimethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00011##
[0712] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-3-(dimethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3)
and dimethylamine hydrochloride. MS (ES) m/z 295.2 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.22N.sub.2O+H+, 295.18049; found (ESI,
[M+H]+), 295.1829.
Example 5
(1RS,2SR)-3-(ethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00012##
[0714] In an analogous manner to EXAMPLE 1, step 3, a solution of
(2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3,
0.42 g, 1.0 mmol) and ethylamine (2 N solution in methanol, 5 mL)
was stirred in a sealed flask at room temperature for 15 hours.
After dilution with a saturated aqueous solution of sodium
bicarbonate, the mixture was extracted with a solution of
dichloromethane/isopropyl alcohol (3/1). The extract was washed
with water, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The crude product was purified on via
Biotage chromatography (FlasH40i, silica, dichloromethane, 5%
methanol/dichloromethane) to give an oil as free base of the
expected product. The free base was dissolved in a minimum amount
of ethanol and treated with a 1N ethereal solution of hydrochloric
acid until the solution was pH=3 followed by diethyl ether. The
product was then crystallized by adding a minimum amount ethyl
acetate to afford the titled compound,
(1RS,2SR)-3-(ethylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride as a tan solid. MS (ES) m/z 295.2 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.22N.sub.2O+H+, 295.18049; found (ESI,
[M+H]+), 295.1797.
Example 6
(1RS,2SR)-1-(1H-indol-1-yl)-3-(isopropylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00013##
[0716] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-1-(1H-indol-1-yl)-3-(isopropylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3)
and isopropylamine. MS (ES) m/z 309.2 ([M+H].sup.+); HRMS: calcd
for C.sub.20H.sub.24N.sub.2O+H+, 309.19614; found (ESI, [M+H]+),
309.1971.
Example 7
(1RS,2SR)-3-(benzylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00014##
[0718] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-3-(benzylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3)
and benzylamine. MS (ES) m/z 357.2 ([M+H].sup.+); HRMS: calcd for
C.sub.24H.sub.24N.sub.2O+H+, 357.19614; found (ESI, [M+H]+),
357.1962.
Example 8
(1RS,2SR)-3-[(cyclohexylmethyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan-2-o-
l Hydrochloride
##STR00015##
[0720] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-3-[(cyclohexylmethyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan-2--
ol hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic
acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step
3) and cyclohexyl methylamine. MS (ES) m/z 363.3 ([M+H].sup.+);
HRMS: calcd for C.sub.24H.sub.30N.sub.2O+H+, 363.24309; found (ESI,
[M+H]+), 363.2421.
Example 9
(1RS,2SR)-3-[(cyclohexylmethyl)amino]-1-(3-methyl-1H-indol-1-yl)-1-phenylp-
ropan-2-ol Hydrochloride
##STR00016##
[0722] In an analogous manner to EXAMPLE 1, step 1
(2RS,3RS)-3-(3-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 3-methylindole and trans-3-phenylglycidol as a yellow
solid. MS (ESI) m/z 282 ([M+H].sup.+).
[0723] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(3-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol. MS
(ESI) m/z 436 ([M+H].sup.+).
[0724] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-3-[(cyclohexylmethyl)amino]-1-(3-methyl-1H-indol-1-yl)-1-phenyl-
propan-2-ol hydro chloride was prepared from
(2RS,3RS)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester and
cyclohexyl methylamine. MS (ES) m/z 377.3 ([M+H].sup.+); HRMS:
calcd for C.sub.25H.sub.32N.sub.2O+H+, 377.25874; found (ESI,
[M+H]+), 377.2577.
Example 10
(1RS,2SR)-3-(isopropylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-o-
l Hydrochloride
##STR00017##
[0726] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-3-(isopropylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2--
ol hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic
acid 3-(3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester
(EXAMPLE 12, step 2) and isopropylamine. MS (ES) m/z 323.2
([M+H].sup.+); HRMS: calcd for C.sub.21H.sub.26N.sub.2O+H+,
323.21179; found (ESI, [M+H]+), 323.2135.
Example 11
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00018##
[0728] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3)
and methylamine (2N solution in methanol). MS (ESI) m/z 281
([M+H].sup.+); HRMS: calcd for C.sub.18H.sub.20N.sub.2O+H+,
281.16484; found (ESI, [M+H]+), 281.166.
Example 12
(1RS,2SR)-3-(ethylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenyl
propan-2-ol Hydrochloride
##STR00019##
[0730] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-3-(ethylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 12,
step 2) and ethylamine (2N solution in methanol). MS (ESI) m/z 309
([M+H].sup.+); HRMS: calcd for C.sub.20H.sub.24N.sub.2O+H+,
309.19614; found (ESI, [M+H]+), 309.198.
Example 13
(1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-piperazin-1-ylpropan-2-ol
Dihydrochloride
##STR00020##
[0732] In an analogous manner to EXAMPLE 1, step 3
(2SR,3RS)-4-(2-hydroxy-3-indol-1-yl-3-phenyl-propyl)-piperazine-1-carboxy-
lic acid tert-butyl ester was prepared from
(2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3,
0.211 g, 0.5 mmol) and tert-butyl-1-piperazine carboxylate (0.19 g,
1.0 mmol). The product was dissolved in diethyl ether (3 mL) and
treated with a 4N solution of hydrochloric acid in dioxane (0.75
mL, 3.0 mmol). The reaction mixture was then stirred at room
temperature for 15 hours, and the crude solid product was filtered
and recrystallized from ethanol with a minimum amount of diethyl
ether to give the titled compound,
(1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-piperazin-1-ylpropan-2-ol
dihydrochloride as a tan solid. MS (ESI) m/z 336 ([M+H].sup.+);
HRMS: calcd for C.sub.21H.sub.25N.sub.3O+H+, 336.20704; found (ESI,
[M+H]+), 336.2085.
Example 14
(1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-[(pyridin-4-ylmethyl)amino]propan-2-
-ol Hydrochloride
##STR00021##
[0734] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-[(pyridin-4-ylmethyl)amino]propan--
2-ol hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic
acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step
3) and pyridine-4-yl-methylamine. MS (ESI) m/z 358 ([M+H].sup.+);
HRMS: calcd for C.sub.23H.sub.23N.sub.3O+H+, 358.19139; found (ESI,
[M+H]+), 358.1928.
Example 15
(1RS,2SR)-1-(5-chloro-1H-indol-1-yl)-1-phenyl-3-piperidin-1-ylpropan-2-ol
Hydrochloride
##STR00022##
[0736] In an analogous manner to EXAMPLE 1, step 1
(2RS,3RS)-3-(5-chloro-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 5-chloroindole and trans-3-phenylglycidol as an oil.
MS (ESI) m/z 302 ([M+H].sup.+).
[0737] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester was prepared
from (2RS,3RS)-3-(5-chloro-indol-1-yl)-3-phenyl-propane-1,2-diol.
MS (ESI) m/z 456 ([M+H].sup.+).
[0738] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-1-(5-chloro-1H-indol-1-yl)-1-phenyl-3-piperidin-1-ylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester and
piperidine. MS m/z 369 ([M+H].sup.+); HRMS: calcd for
C.sub.22H.sub.25ClN.sub.2O+H+, 369.17282; found (ESI, [M+H]+),
369.1725.
Example 16
(1RS,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00023##
[0740] Step 2. To a solution of
(2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol (EXAMPLE 1, step
1, 1.83 g, 6.9 mmol) in anhydrous pyridine (25 mL), p-nitrobenzoyl
chloride (1.3 g, 6.9 mmol) in 1 mL of pyridine was added at
-10.degree. C. dropwise. After stirring for 30 minutes, the
reaction mixture was cooled with an ice bath and quenched with
water and a 2N aqueous solution of hydrochloric acid until the
solution was pH=3 and extracted with ethyl acetate. The extract was
washed with water, dried over anhydrous sodium sulfate and
concentrated to give (2RS,3RS)-4-nitro-benzoic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester quantitatively as a
yellow solid. MS (ESI) m/z 417 ([M+H].sup.+).
[0741] Step 3. To a solution of (2RS, 3RS)-4-nitro-benzoic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester and triethylamine (1.4
mL, 10.5 mmol) in dichloromethane (20 mL) was added methanesulfonyl
chloride (0.59 mL, 7.6 mmol) dropwise at 0-5.degree. C. with
stirring. After stirring for 30 minutes, the mixture was washed
with a 1N aqueous solution of hydrochloric acid, 5% aqueous sodium
bicarbonate, and water, dried over anhydrous sodium sulfate,
filtered, and concentrated to give a light yellow fluffy solid. The
crude product was recrystallized from dichloromethane with a
minimum amount of diethyl ether to give (2RS,3RS)-4-nitro-benzoic
acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester as a
yellow solid. MS (ESI) m/z 495 ([M+H].sup.+).
[0742] Step 4. A solution of (2RS,3RS)-4-nitro-benzoic
acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester in
dioxane (30 mL) and a 2N aqueous solution of sodium hydroxide (15
mL) were stirred at room temperature for 4 hours. The mixture was
diluted with water and extracted with ethyl acetate. The extract
was washed with 5% aqueous sodium carbonate and water, dried over
anhydrous sodium sulfate, filtered, and concentrated to give
(1RS,2SR)-1-(oxiranyl-phenyl-methyl)-1H-indole as an oil. MS (ESI)
m/z 250 ([M+H].sup.+).
[0743] Step 5. (1RS,2SR)-1-(oxiranyl-phenyl-methyl)-1H-indole was
treated with 5 mL of methylamine (2N solution in methanol) with
stirring at room temperature for 15 hours. The reaction mixture was
concentrated in vacuo and the crude product was recrystallized form
dichloromethane. The free base of the expected product was
dissolved in a minimum amount of dichloromethane, treated with a 1N
ethereal solution of hydrochloric acid until the solution was pH=3.
The solid product was then recrystallized by adding an additional
diethyl ether to give
(1RS,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride as a light tan solid. MS m/z 281 ([M+H].sup.+); HRMS:
calcd for C.sub.18H.sub.20N.sub.2O+H+, 281.16484; found (ESI,
[M+H]+), 281.1654.
Example 17
(1RS,2SR)-3-amino-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00024##
[0745] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-3-amino-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3,
0.42 g, 1.0 mmol) in a minimum amount of methanol and an excess of
a 30% aqueous solution of ammonium hydroxide. The crude product was
dissolved in n-hexane and filtered to give a white solid as a free
base. The free base of the product was dissolved in a minimum
amount of ethanol and treated with a 1N solution of ethereal
hydrochloric acid until the solution was pH=3 followed by diethyl
ether. The product was then crystallized by adding a minimum amount
of ethyl acetate to afford the titled compound as a tan solid. MS
(ESI) m/z 267 ([M+H].sup.+); HRMS: calcd for
C.sub.17H.sub.18N.sub.2O+H+, 267.14919; found (ESI, [M+H]+),
267.1493.
Example 18
(1RS,2SR)-3-(ethylamino)-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00025##
[0747] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-3-(ethylamino)-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 2,
step 2) and ethylamine (2N solution in methanol). MS (ES) m/z 313.2
([M+H].sup.+); HRMS: calcd for C.sub.19H.sub.21FN.sub.2O+H+,
313.17107; found (ESI, [M+H]+), 313.1706.
Example 19
(1RS,2SR)-3-amino-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00026##
[0749] In an analogous manner to EXAMPLE 17,
(1RS,2SR)-3-amino-1-(5-fluoro-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS, 3RS)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 2,
step 2) and a 30% aqueous solution of ammonium hydroxide as a white
solid. MS (ES) m/z 285.2 ([M+H].sup.+); HRMS: calcd for
C.sub.17H.sub.17FN.sub.2O+H+, 285.13977; found (ESI, [M+H]+),
285.1403.
Example 20
(1RS,2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00027##
[0751] In an analogous manner to EXAMPLE
5,(1RS,2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-o-
l hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 2,
step 2) obtained and methylamine (2N solution in methanol). MS
(ESI) m/z 299 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19FN.sub.2O+H+, 299.15542; found (ESI, [M+H]+),
299.1564.
Example 21
(1RS,2SR)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenyl
propan-2-ol Hydrochloride
##STR00028##
[0753] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS, 3RS)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 10,
step 2) and methylamine (2N solution in methanol). MS (ESI) m/z 295
([M+H].sup.+); HRMS: calcd for C.sub.19H.sub.22N.sub.2O+H+,
295.18049; found (ESI, [M+H]+), 295.1816.
Example 22
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00029##
[0755] In an analogous manner to EXAMPLE 1, step 1
(2R,3R)-3-indol-1-yl-3-phenyl-propane-1,2-diol was prepared from
indole and [(2S,3S)-3-phenyloxiran-2-yl]methanol as an oil. MS
(ESI) m/z 286 ([M+H].sup.+).
[0756] In an analogous manner to EXAMPLE 1, step 2
(2R,3R)-toluene-4-sulfonic acid
3-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was prepared from
(2R,3R)-3-indol-1-yl-3-phenyl-propane-1,2-diol. MS (ESI) m/z 440
([M+H].sup.+).
[0757] In an analogous manner to EXAMPLE 5,
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2R,3R)-toluene-4-sulfonic acid
3-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and methylamine (2N
solution in methanol) as a white solid. CD/MeOH=(+); e/e=99.9% as
determined by chiral HPLC; MS (ESI) m/z 281 ([M+H].sup.+); HRMS:
calcd for C.sub.18H.sub.20N.sub.2O+H+, 281.16484; found (ESI,
[M+H]+), 281.1649.
Example 23
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00030##
[0759] Racemic
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
(EXAMPLE 11) was dissolved in methanol. The resulting solution was
injected onto the Supercritical Fluid Chromatography instrument.
The baseline resolved enantiomers, using the conditions described
below, were collected. The enantiomeric purity of each enantiomer
was determined under the same Supercritical Fluid Chromatography
conditions using a Chiralcel OJ-H 5u, 250 mm.times.4.6 mm ID column
at 2.0 mL/minutes flow rate using Analytical Supercritical Fluid
Chromatography (Berger Instruments, Inc. Newark, Del. USA).
[0760] SFC Instrument: Berger MultiGram Prep SFC (Berger
Instruments, Inc. Newark, Del. 19702. [0761] Column: Chiralcel
OJ-H; 5u; 250 mm L.times.20 mm ID (Chiral Technologies, Inc, Exton,
Pa., USA) [0762] Column temperature: 35.degree. C. [0763] SFC
Modifier: 20% MeOH with 1% diethylamine [0764] Flow rate: 50 mL/min
[0765] Outlet Pressure: 100 bar [0766] Detector: UV at 218 nm
[0767]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol was
isolated as a slower retention time peak with (-) rotation of
chiral detection (CD) and e/e=99.4% as determined by chiral HPLC.
The isolated free base was concentrated in vacuo, dissolved in
minimum amount of ethanol and treated with a 1N ethereal solution
of hydrochloric acid until the solution was pH=3 followed by
diethyl ether. The product was then crystallized by adding a
minimum amount of ethyl acetate to afford the titled compound as a
white solid of hydrochloride salt; MS (ESI) m/z 281 ([M+H].sup.+);
HRMS: calcd for C18H20N2O+H+, 281.16484; found (ESI, [M+H]+),
281.1646.
Example 24
(1RS,2SR)-3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00031##
[0769] In an analogous manner to EXAMPLE 17,
(1RS,2SR)-3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS, 3RS)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 9,
step 2) and a 30% aqueous solution of ammonium hydroxide as a tan
solid. MS (ES) m/z 281.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.20N.sub.2O+H+, 281.16484; found (ESI, [M+H]+),
281.1645.
Example 25
(1RS,2SR)-3-[ethyl(methyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00032##
[0771] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-3-[ethyl(methyl)amino]-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from
(1RS,2SR)-3-(methylamino)-1-(1H-indol-1-yl)-1-phenylpropan-2-ol
(EXAMPLE 11) and ethylamine (2N solution in methanol) as a tan
solid. MS (ES) m/z 309.0 ([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.24N.sub.2O+H+, 309.19614; found (ESI, [M+H]+),
309.1955.
Example 26
(1RS,2SR)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00033##
[0773] In an analogous manner to EXAMPLE 1, step 1
(2RS,3RS)-3-(5-chloro-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 5-chloroindole and trans-3-phenylglycidol as an oil.
MS (ESI) m/z 302 ([M+H].sup.+).
[0774] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester was prepared
from (2RS,3RS)-3-(5-chloro-indol-1-yl)-3-phenyl-propane-1,2-diol.
MS (ESI) m/z 456 ([M+H].sup.+).
[0775] In an analogous manner to EXAMPLE 5, step 3
(1RS,2SR)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol). MS (ESI) m/z 315
([M+H].sup.+); HRMS: calcd for C.sub.18H.sub.19ClN.sub.2O+H+,
315.12587; found (ESI, [M+H]+), 315.1258.
Example 27
(1RS,2RS)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-1-ol
Hydrochloride
##STR00034##
[0777] In an analogous manner to EXAMPLE 16, step 2
(2RS,3RS)-4-nitro-benzoic acid
3-(5-chloro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(5-chloro-indol-1-yl)-3-phenyl-propane-1,2-diol
(EXAMPLE 1, step 1). MS (ESI) m/z 451 ([M+H].sup.+).
[0778] In an analogous manner to EXAMPLE 16, step 3
(2RS,3RS)-4-nitro-benzoic acid
3-(5-chloro-indol-1-yl)-2-methanesulfonyloxy-3-phenyl-propyl ester
was prepared from (2RS,3RS)-4-nitro-benzoic acid
3-(5-chloro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. MS (ESI)
m/z 529 ([M+H].sup.+).
[0779] In an analogous manner to EXAMPLE 16, step 4
(1RS,2SR)-5-chloro-1-(oxiranyl-phenyl-methyl)-1H-indole was
prepared from (2RS,3RS)-4-nitro-benzoic acid
3-(5-chloro-indol-1-yl)-2-methanesulfonyloxy-3-phenyl-propyl ester.
MS (ESI) m/z 284 ([M+H].sup.+).
[0780] In an analogous manner to EXAMPLE 16, step 5
(1RS,2RS)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride as a tan solid. MS (ESI) m/z 315 ([M+H].sup.+); HRMS:
calcd for C.sub.18H.sub.19ClN.sub.2O+H+, 315.12587; found (ESI,
[M+H]+), 315.1276.
Example 28
1-[(1RS,2SR)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-3-carboni-
trile hydrochloride
##STR00035##
[0782] In an analogous manner to EXAMPLE 1, step 1
(2RS,3RS)-3-(3-cyano-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 3-cyanoindole and trans-3-phenylglycidol as an oil.
MS (ESI) m/z 293 ([M+H].sup.+).
[0783] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(3-cyano-indol-1-yl-2-hydroxy-3-phenyl-propyl ester was prepared
from (2RS,3RS)-3-(3-cyano-indol-1-yl)-3-phenyl-propane-1,2-diol. MS
(ESI) m/z 447 ([M+H].sup.+).
[0784] In an analogous manner to EXAMPLE 1, step 3
(1RS,2SR)-1-(3-cyano-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpr-
opan-2-ol hydrochloride was prepared from (2
RS,3RS)-toluene-4-sulfonic acid
3-(3-cyano-indol-1-yl-2-hydroxy-3-phenyl-propyl ester as a white
solid. MS (ESI) m/z 306 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.19N.sub.3O+H+, 306.16009; found (ESI, [M+H]+),
306.1614.
Example 29
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00036##
[0786] Racemic
(1RS,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
(EXAMPLE 16) was dissolved in methanol. The resulting solution was
injected onto the Supercritical Fluid Chromatography instrument.
The baseline resolved enantiomers, using the conditions described
below, were collected. The enantiomeric purity of each enantiomer
was determined under the same Supercritical Fluid Chromatography
conditions using a Chiralcel OJ-H 5u, 250 mm.times.4.6 mm ID column
at 2.0 mL/minutes flow rate using Analytical Supercritical Fluid
Chromatography (Berger Instruments, Inc. Newark, Del. USA). [0787]
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del. 19702. [0788] Column: Chiralcel OJ-H; 5u; 250 mm
L.times.20 mm ID (Chiral Technologies, Inc, Exton, Pa., USA) [0789]
Column temperature: 35.degree. C. [0790] SFC Modifier: 20% MeOH
with 1% Ethanesulfonic acid [0791] Flow rate: 50 mL/min [0792]
Outlet Pressure: 100 bar [0793] Detector: UV at 220 nm
[0794]
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol was
isolated as a faster retention time peak with (+) rotation of
chiral detection (CD) and e/e=99.9% as determined by chiral
HPLC.
[0795] In an analogous manner as EXAMPLE 23, the titled compound
was afforded as an off white solid of hydrochloride salt; MS (ESI)
m/z 306 ([M+H].sup.+); HRMS: calcd for C18H20N2O+H+, 281.16484;
found (ESI, [M+H]+), 281.1654.
Example 30
(1S,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00037##
[0797] In an analogous manner to EXAMPLE 29,
(1S,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol was
isolated as a slower retention time peak with (-) rotation of
chiral detection (CD) and e/e=99.9% as determined by chiral
HPLC.
[0798] In an analogous manner as EXAMPLE 23, the titled compound
was afforded as a white solid of hydrochloride salt; MS (ESI) m/z
306 ([M+H].sup.+); HRMS: calcd for C18H20N2O+H+, 281.16484; found
(ESI, [M+H]+), 281.1655.
Example 31
(1S,2R)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00038##
[0800] In an analogous manner to EXAMPLE 1, step 1
(2S,3S)-3-(3-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 3-methylindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 282 ([M+H].sup.+).
[0801] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(3-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol. MS (ESI)
m/z 436 ([M+H].sup.+).
[0802] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol) as a white solid.
[.quadrature.]D.sup.25/MeOH=+116; CD/MeOH=(-); MS (ESI) m/z 295
([M+H].sup.+); HRMS: calcd for C.sub.19H.sub.22N.sub.2O+H+,
295.18049; found (ESI, [M+H]+), 295.1816.
Example 32
(1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylp-
ropan-2-ol Dihydrochloride
##STR00039##
[0804] A mixture of 3,4-dihydro-2H-benzo[1,4]oxazine (2.027 g 15.00
mmol) and trans-ethyl-3-phenylglycidate (2.883 g, 15.00 mmol) was
stirred at 135.degree. C. for 12 hours. After cooling, the viscous
liquid was purified via Biotage Horizon (FLASH 40 M, silica, 10%,
20%, 30% EtOAc/hexane) and recrystallized (minimal warm
chloroform/hexane/-20.degree. C.) to yield 4.261 g (87%) ethyl
(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropan-
oate as a white solid. MS (ESI) m/z 328.0 ([M+H].sup.+).
[0805] A mixture of ethyl
(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropan-
oate (283 mg, 0.864 mmol) and ethanolic methylamine solution (5 mL,
33% in ethanol) was stirred at 70.degree. C. in a sealed tube for 5
hours. After cooling, all volatiles were removed under reduced
pressure. The resulting yellow solid was purified via Biotage
Horizon (FLASH 12 S, silica, 20%, 35%, 50% EtOAc/hexane) to yield
235 mg (87%)
(2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3
phenylpropanamide as a white solid. MS (ESI) m/z 311.0
([M-H].sup.-).
[0806] A solution of (2RS,3
RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3
phenylpropanamide (216 mg, 0.692 mmol) in dry tetrahydrofuran (3
mL) under nitrogen was treated dropwise with a solution of borane
(1.0 M in tetrahydrofuran, 3.50 mL, 3.50 mmol), and the resulting
solution was stirred at 70.degree. C. for 2 hours. After cooling in
an ice bath, the reaction mixture was treated with a 2N aqueous
solution of hydrochloric acid (1 mL), and the resulting mixture was
heated at 50.degree. C. for 30 minutes. Tetrahydrofuran was removed
under reduced pressure, and the aqueous residue was dissolved in
water (5 mL) and washed with diethyl ether (10 mL). The aqueous
layer was made alkaline with solid potassium carbonate and
extracted with ethyl acetate (2.times.10 mL). The combined organic
extracts were washed with brine, dried (sodium sulfate) and
concentrated under reduced pressure to yield 202 mg (98%)
(1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenyl-
propan-2-ol as a colorless oil. This oil was dissolved in ethanol
(1 mL) and treated with a solution of hydrochloric acid (0.5 mL, 4M
in 1,4-dioxane). All volatiles were again removed under reduced
pressure. The resulting white solid was recrystallized (minimal
warm ethanol/ethyl ether/-20.degree. C.) to yield 105 mg (41%)
(1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenyl-
propan-2-ol dihydrochloride as a white solid. MS (ESI) m/z 299.0
([M+H].sup.+); HRMS: calcd for C.sub.18H.sub.22N.sub.2O.sub.2+H+,
299.17540; found (ESI, [M+H]+), 299.1755.
Example 33
(1S,2R)-1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00040##
[0808] Step 1: A suspension of sodium hydride (60% in mineral oil,
4.0 g, 100 mmol) in tetrahydrofuran (600 mL) was treated dropwise
with diethyl ethoxycarbonylmethylphosphonate (20 mL, 100 mmol) at
23.degree. C. After 1 hour s,3-chlorobenzaldehyde (9.3 mL, 82 mmol)
was added. After an additional 1 hour, the reaction was quenched
with water (20 mL) and concentrated under vacuum to remove
tetrahydrofuran. The residue was taken up in ethyl acetate (300
mL), washed with water (5.times.300 mL) and brine (1.times.300 mL),
dried (magnesium sulfate) and concentrated under vacuum to provide
(2E)-3-(3-chlorophenyl)-acrylic acid ethyl ester (18 g,
quantitative) as a clear, pale yellow oil. MS (ESI) m/z 210
([M+H].sup.+).
[0809] Step 2: (2E)-3-(3-Chlorophenyl)-acrylic acid ethyl ester
(17.6 g, 82 mmol) was dissolved in dry dichloromethane (300 mL),
cooled to -78.degree. C. and treated with a solution of
di-iso-butylaluminum hydride (1.0 M solution in hexane, 250 mL, 250
mmol) over 20 minutes. After 1.5 hours total, the reaction was
quenched with methanol (75 mL) at -78.degree. C., warmed to
23.degree. C. and treated with a saturated aqueous solution of
potassium sodium tartrate (300 mL). The aqueous phase was separated
and extracted with dichloromethane (2.times.300 mL). The combined
extracts were washed with a saturated aqueous solution of sodium
tartrate (450 mL), dried (sodium sulfate) and concentrated under
vacuum to provide a cloudy yellow oil (14.6 g) that was
pre-adsorbed on silica gel (25 g). Flash column chromatography
(silica 250 g, 10%, 20% ethyl acetate/hexanes) provided
(2E)-3-(3-chlorophenyl)prop-2-en-1-ol (12.4 g, 90%) as a clear,
colorless oil. MS (ESI) m/z 151 ([M+H-H.sub.2O].sup.+).
[0810] Step 3: In an analogous manner to EXAMPLE 117, step 4,
[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol was prepared from
(2E)-3-(3-chlorophenyl)prop-2-en-1-ol. MS (ESI) m/z 167
([M+H-H.sub.2O].sup.+).
[0811] Step 4 (Method A): In an analogous manner to EXAMPLE 117,
step 5,
(2S,3S)-3-(3-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol was
prepared from 1H-indole and
[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol. MS (ES) m/z 302
([M+H].sup.+).
[0812] Step 4a (Method B):
[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol (4.8 g, 26 mmol)
and indoline (d 1.063, 2.9 mL, 26 mmol) were heated neat at
135.degree. C. in a sealed flask. After 1.5 hours, the cooled
mixture was pre-adsorbed on silica gel (25 g). Flash column
chromatography (silica 375 g, 20%, 40%, 80% ethyl acetate/hexanes)
provided
(2S,3S)-3-(3-chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol
(5.8 g, 73%) as a white solid. MS (ES) m/z 304 ([M+H].sup.+).
[0813] Step 4b (Method B): A solution of
(2S,3S)-3-(3-chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol
(5.8 g, 19 mmol) in ca. 1:1 (v/v) toluene-dichloromethane (200 mL)
was treated with a solution of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.4 g, 19 mmol) in
toluene (100 mL) at 0.degree. C. After 30 minutes, the mixture was
diluted with ethyl acetate (1 L) and washed with 5% aqueous sodium
carbonate (4.times.1 L), water (1 L) and brine (1 L), dried
(magnesium sulfate) and concentrated under vacuum to give a dark
oil (5.4 g) that was pre-adsorbed on silica gel (15 g). Flash
column chromatography (silica 235 g, 20%, 40% ethyl
acetate/hexanes) provided
(2S,3S)-3-(3-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol, (4.7
g, 82%) as a cloudy yellow oil. MS (ES) m/z 302 ([M+H].sup.+).
[0814] Step 5: In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared
from (2S,3S)-3-(3-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol.
MS (ES) m/z 456 ([M+H].sup.+).
[0815] Step 6: (2S,3S)-Toluene-4-sulfonic acid
3-(3-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester (0.60 g, 1.2
mmol) was treated with a solution of methylamine in methanol (2.0
M, 3 mL, 6 mmol) and the solution was stirred at 23.degree. C. for
18 hours. At this time, the solution was concentrated under vacuum
and dissolved in diethyl ether (50 mL). The organic solution was
washed with a 1 N aqueous solution of sodium hydroxide (50 mL),
water (50 mL) and brine (50 mL), dried (sodium sulfate) and
concentrated under vacuum to provide an orange foam (0.30 g) that
was purified by reverse phase HPLC (90:10 water-acetonitrile to
50:50 water-acetonitrile containing 0.1% trifluoroacetic acid @ 20
mL/min). The product fractions were concentrated under vacuum to
remove acetonitrile and the aqueous solution was basified with a 2N
aqueous solution of ammonium hydroxide. The resulting milky
suspension was extracted with ethyl acetate (200 mL) and the
organic phase was washed with water (200 mL) and brine (100 mL),
dried (sodium sulfate) and concentrated under vacuum. The residue
was dissolved in absolute ethanol (4 mL), treated with a 4 M
hydrochloric acid in 1,4-dioxane (1.3 eq) and stirred for 10
minutes. The solution was concentrated under vacuum, then dissolved
in absolute ethanol (3 mL) and left standing at 23.degree. C.
overnight. Vacuum filtration provided
(1S,2R)-1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride (62 mg, 5% for 3 steps) as a white crystalline solid.
HRMS calcd for C.sub.18H.sub.19ClN.sub.2O+H.sup.+, 315.12587; found
(ESI) 315.1267 ([M+H].sup.+).
Example 34
(1S,2R)-1-(4-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00041##
[0817] In an analogous manner to EXAMPLE 33, step 1
(2E)-3-(4-chlorophenyl)-acrylic acid ethyl ester was prepared from
diethyl ethoxycarbonylmethylphosphonate and 4-chlorobenzaldehyde.
MS (ESI) m/z 210 ([M+H].sup.+).
[0818] In an analogous manner to EXAMPLE 33, step 2
(2E)-3-(4-chlorophenyl)prop-2-en-1-ol was prepared from
(2E)-3-(4-chlorophenyl)-acrylic acid ethyl ester. MS (ESI) m/z 151
([M+H-H.sub.2O].sup.+).
[0819] In an analogous manner to EXAMPLE 117, step 4,
[(2R,3R)-3-(4-chlorophenyl)oxiran-2-yl]methanol was prepared from
(2E)-3-(4-chlorophenyl)prop-2-en-1-ol. MS (ESI) m/z 167
([M+H-H.sub.2O].sup.+); [.quadrature..quadrature..sub.D +41 (c
0.0121 g/mL, DMSO); 99.2% ee.
[0820] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(4-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol was
prepared from 1H-indole and
[(2R,3R)-3-(4-chlorophenyl)oxiran-2-yl]methanol. MS (ES) m/z 302
([M+H].sup.+).
[0821] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(4-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared
from (2S,3S)-3-(4-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol.
MS (ES) m/z 456 ([M+H].sup.+).
[0822] In an analogous manner to EXAMPLE 33, step 6
(1S,2R)-1-(4-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(4-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester and
methylamine (2 N solution in methanol). HRMS: calcd for
C.sub.18H.sub.19ClN.sub.2O+H.sup.+, 315.12587; found (ESI) 315.124
([M+H].sup.+).
Example 35
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy)phenyl]pr-
opan-2-ol Hydrochloride
##STR00042##
[0824] In an analogous manner to EXAMPLE 33, step 1,
(2E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid ethyl ester was
prepared from diethyl ethoxycarbonylmethylphosphonate and
3-(trifluoromethoxy)benzaldehyde. MS (ES) m/z 261
([M+H].sup.+).
[0825] In an analogous manner to EXAMPLE 33, step 2,
(2E)-3-[3-(trifluoromethoxy)phenyl]prop-2-en-1-ol was prepared from
(2E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid ethyl ester. MS
(ES) m/z 201 ([M+H-H.sub.2O].sup.+).
[0826] In an analogous manner to EXAMPLE 117, step 4,
{(2R,3R)-3-[3-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol was
prepared from (2E)-3-[3-(trifluoromethoxy)phenyl]prop-2-en-1-ol. MS
(ES) m/z 217 ([M+H-H.sub.2O].sup.+);
[.quadrature.].sub.D.sup.25=+30.degree. (c=0.0118 g/mL, DMSO);
84.4% ee.
[0827] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(1H-indol-1-yl)-3-[3-(trifluoromethoxy)phenyl]propane-1,2-diol
was prepared from 1H-indole and
{(2R,3R)-3-[3-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol. MS
(ES) m/z 352 ([M+H].sup.+).
[0828] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(3-trifluoromethoxy-phenyl)-propyl ester
was prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-[3-(trifluoromethoxy)phenyl]propane-1,2-diol.
MS (ES) m/z 506 ([M+H].sup.+).
[0829] In an analogous mannerto EXAMPLE 33, step 6
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy)phenyl]p-
ropan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(3-trifluoromethoxy-phenyl)-propyl ester
and methylamine (2 N in methanol). MS (ES) m/z 365
([M+H].sup.+).
Example 36
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]pr-
opan-2-ol Hydrochloride
##STR00043##
[0831] Step 1: In an analogous manner to EXAMPLE 33, step 1,
(2E)-3-(2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester was
prepared from diethyl ethoxycarbonylmethylphosphonate and
2-(trifluoromethoxy)benzaldehyde. MS (ES) m/z 261
([M+H].sup.+).
[0832] Step 2: In an analogous manner to EXAMPLE 33, step 2,
(2E)-3-[2-(trifluoromethoxy)phenyl]prop-2-en-1-ol was prepared from
(2E)-3-(2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester. MS
(ES) m/z 201 ([M+H-H.sub.2O].sup.+).
[0833] Step 3: A solution of
(2E)-3-[2-(trifluoromethoxy)phenyl]prop-2-en-1-ol (3.9 g, 18 mmol)
in dichloromethane (90 mL) was treated with
meta-chloroperoxybenzoic acid (77%, 8.0 g, 36 mmol) at 23.degree.
C. After 5 hours, the reaction was quenched with a 1 N aqueous
solution of sodium hydroxide (200 mL) with vigorous stirring and
the phases were separated. The aqueous phase was extracted with
diethyl ether (2.times.100 mL). The combined organic phases were
washed with water (3.times.100 mL), dried (sodium sulfate) and
concentrated under vacuum to provided a clear, colorless oil (3.8
g) that was pre-adsorbed on silica gel (6 g). Flash column
chromatography (silica 60 g, 10%, 20% ethyl acetate/hexanes)
provided
{(2RS,3RS)-3-[2-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol (2.4
g, 57%) as a white solid. MS (ES) m/z 217
([M+H-H.sub.2O].sup.+).
[0834]
{(2RS,3RS)-3-[2-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol was
dissolved in methanol. The resulting solution was injected onto the
Supercritical Fluid Chromatography instrument, and the baseline
resolved enantiomers were collected using the conditions described
below. The enantiomeric purity of each enantiomer was determined
under the same Supercritical Fluid Chromatography conditions using
a Chiralpak AS-H 5u, 250 mm.times.4.6 mm ID column at 2.0
mL/minutes flow rate using Analytical Supercritical Fluid
Chromatography (Berger Instruments, Inc. Newark, Del. USA).
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del. 19702.
Column: Chiralpak AS-H; 5u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa., USA)
[0835] Column temperature: 35.degree. C.
SFC Modifier: 5% IPA/95% CO2
[0836] Flow rate: 35 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[0837] {(2R,3R)-3-[2-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol
was isolated as peak 1. MS (ES) m/z 217 ([M+H-H.sub.2O].sup.+);
[.quadrature.].sub.D.sup.25=+19.40 (c=0.0102 g/mL, DMSO); >99.9%
ee.
[0838] {(2S,3S)-3-[2-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol
was isolated as peak 2. MS (ES) m/z 217 ([M+H-H.sub.2O].sup.+);
[.quadrature.].sub.D.sup.25=-15.70 (c=0.0125 g/mL, DMSO); 95.8%
ee.
[0839] Step 4: In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(1H-indol-1-yl)-3-[2-(trifluoromethoxy)phenyl]propane-1,2-diol
was prepared from 1H-indole and
{(2R,3R)-3-[2-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol,
substituting sodium tert-butoxide in place of potassium hydride. MS
(ES) m/z 352 ([M+H].sup.+).
[0840] Step 5: In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(2-trifluoromethoxy-phenyl)-propyl ester
was prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-[2-(trifluoromethoxy)phenyl]propane-1,2-diol.
MS (ES) m/z 506 ([M+H].sup.+).
[0841] Step 6: In an analogous manner to EXAMPLE 33, step 6
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]p-
ropan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(2-trifluoromethoxy-phenyl)-propyl ester
and methylamine (2 N in methanol). MS (ES) m/z 365
([M+H].sup.+).
Example 37
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]pr-
opan-2-ol Hydrochloride
##STR00044##
[0843] In an analogous manner to EXAMPLE 117, step 5,
(2R,3R)-3-(1H-indol-1-yl)-3-[2-(trifluoromethoxy)phenyl]propane-1,2-diol
was prepared from 1H-indole and
{(2S,3S)-3-[2-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol
(EXAMPLE 36, step 3) substituting sodium tert-butoxide in place of
potassium hydride. MS (ES) m/z 352 ([M+H].sup.+).
[0844] In an analogous manner to EXAMPLE 1, step 2,
(2R,3R)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(2-trifluoromethoxy-phenyl)-propyl ester
was prepared from
(2R,3R)-3-(1H-indol-1-yl)-3-[2-(trifluoromethoxy)phenyl]propane-1,2-diol.
MS (ES) m/z 506 ([M+H].sup.+).
[0845] In an analogous manner to EXAMPLE 33, step 6
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy)phenyl]p-
ropan-2-ol hydrochloride was prepared from
(2R,3R)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(2-trifluoromethoxy-phenyl)-propyl ester
and methylamine (2 N in methanol). MS (ES) m/z 365
([M+H].sup.+).
Example 38
(1S,2R)-1-(2-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00045##
[0847] In an analogous manner to EXAMPLE 33, step 1,
(2E)-3-(2-chlorophenyl)-acrylic acid ethyl ester was prepared from
diethyl ethoxycarbonylmethylphosphonate and 2-chlorobenzaldehyde.
MS (ESI) m/z 210 ([M+H].sup.+).
[0848] In an analogous manner to EXAMPLE 33, step 2,
(2E)-3-(2-chlorophenyl)prop-2-en-1-ol was prepared from
(2E)-3-(2-chlorophenyl)-acrylic acid ethyl ester. MS (ESI) m/z 151
([M+H-H.sub.2O].sup.+).
[0849] In an analogous manner to EXAMPLE 36, step 3,
[(2RS,3RS)-3-(2-chlorophenyl)oxiran-2-yl]methanol was prepared from
(2E)-3-(2-chlorophenyl)prop-2-en-1-ol.
[0850] [(2RS,3RS)-3-(2-chlorophenyl)oxiran-2-yl]methanol was
dissolved in methanol. The resulting solution was injected (50
mg/injection) onto the Supercritical Fluid Chromatography
instrument, and the baseline resolved enantiomers were collected
using the conditions described below. The enantiomeric purity of
each enantiomer was determined under the same Supercritical Fluid
Chromatography conditions using a Chiralpak AD-H 5u, 250
mm.times.4.6 mm ID column at 2.0 mL/minutes flow rate using
Analytical Supercritical Fluid Chromatography (Berger Instruments,
Inc. Newark, Del. USA).
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del. 19702.
Column: Chiralpak AD-H; 5u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa., USA)
[0851] Column temperature: 35.degree. C.
SFC Modifier: 20% MeOH/80% CO2
[0852] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[0853] [(2S,3S)-3-(2-chlorophenyl)oxiran-2-yl]methanol was isolated
as peak 1. MS (ES) m/z 167 ([M+H-H.sub.2O].sup.+);
[.quadrature.].sub.D.sup.25=+2.6.degree. (c=0.0153 g/mL, DMSO);
>99.8% ee.
[0854] [(2R,3R)-3-(2-chlorophenyl)oxiran-2-yl]methanol was isolated
as peak 2. MS (ES) m/z 167 ([M+H-H.sub.2O].sup.+);
[.quadrature.].sub.D.sup.25=-2.5.degree. (c=0.0139 g/mL, DMSO);
>99.8% ee.
[0855] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(2-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol was
prepared from 1H-indole and
[(2R,3R)-3-(2-chlorophenyl)oxiran-2-yl]methanol, substituting
sodium tert-butoxide in place of potassium hydride. MS (ES) m/z 302
([M+H].sup.+).
[0856] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(2-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared
from (2S,3S)-3-(2-chlorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol.
MS (ES) m/z 456 ([M+H].sup.+).
[0857] In an analogous manner to EXAMPLE 33, step 6
(1S,2R)-1-(2-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(2-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester and
methylamine (2 N in methanol). MS (ES) m/z 315 ([M+H].sup.+).
Example 39
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-
propan-2-ol Hydrochloride
##STR00046##
[0859] Step 1: In an analogous manner to EXAMPLE 33, step 1,
(2E)-3-(4-trifluoromethoxy-phenyl)-acrylic acid ethyl ester was
prepared from diethyl ethoxycarbonylmethylphosphonate and
4-(trifluoromethoxy)benzaldehyde. MS (ES) m/z 261
([M+H].sup.+).
[0860] Step 2: In an analogous manner to EXAMPLE 33, step 2,
(2E)-3-[4-(trifluoromethoxy)phenyl]prop-2-en-1-ol was prepared from
(2E)-3-(4-trifluoromethoxy-phenyl)-acrylic acid ethyl ester. MS
(ES) m/z 201 ([M+H-H.sub.2O].sup.+).
[0861] Step 3: In an analogous manner to EXAMPLE 36, step 3,
{(2RS,3RS)-3-[4-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol was
prepared from (2E)-3-[4-(trifluoromethoxy)phenyl]prop-2-en-1-ol. MS
(ES) m/z 217 ([M+H-H.sub.2O].sup.+).
[0862] Step 4: In an analogous manner to EXAMPLE 33, step 4a
(Method B),
(2RS,3RS)-3-(2,3-dihydro-1H-indol-1-yl)-3-[4-(trifluoromethoxy)phenyl]pro-
pane-1,2-diol was prepared from indoline and
{(2RS,3RS)-3-[4-(trifluoromethoxy)phenyl]oxiran-2-yl}methanol. MS
(ES) m/z 354 ([M+H].sup.+).
[0863] Step 5: In an analogous manner to EXAMPLE 33, step 4b
(Method B),
(2RS,3RS)-3-(1H-indol-1-yl)-3-[4-(trifluoromethoxy)phenyl]propane-1,2-dio-
l was prepared from
(2RS,3RS)-3-(2,3-dihydro-1H-indol-1-yl)-3-[4-(trifluoromethoxy)phenyl]pro-
pane-1,2-diol. MS (ES) m/z 352 ([M+H].sup.+).
[0864] Step 6: In an analogous manner to EXAMPLE 1, step 2,
(2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(4-trifluoromethoxy-phenyl)-propyl ester
was prepared from
(2RS,3RS)-3-(1H-indol-1-yl)-3-[4-(trifluoromethoxy)phenyl]propane-1,2-dio-
l. MS (ES) m/z 506 ([M+H].sup.+).
[0865] Step 7: In an analogous manner to EXAMPLE 33, step 6 (Method
B),
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl-
]propan-2-ol hydrochloride was prepared from
(2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-indol-1-yl-3-(4-trifluoromethoxy-phenyl)-propyl ester
and methylamine (2 N in methanol). MS (ES) m/z 365
([M+H].sup.+).
Example 40
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]pr-
opan-2-ol Hydrochloride
##STR00047##
[0867] Step 1:
(1RS,2SR)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl-
]propan-2-ol hydrochloride (EXAMPLE 39, step 7) was dissolved in
methanol. The resulting solution was injected (35 mg/injection)
onto the Supercritical Fluid Chromatography instrument, and the
baseline resolved enantiomers were collected using the conditions
described below. The enantiomeric purity of each enantiomer was
determined under the same Supercritical Fluid Chromatography
conditions using a Chiralpak AD-H 5u, 250 mm.times.4.6 mm ID column
at 2.0 mL/minutes flow rate using Analytical Supercritical Fluid
Chromatography (Berger Instruments, Inc. Newark, Del. USA).
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del. 19702.
Column: Chiralpak AD-H; 5u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa., USA)
[0868] Column temperature: 35.degree. C.
SFC Modifier: 25% MeOH w/1.0% DEA/75% CO2
[0869] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[0870]
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)ph-
enyl]propan-2-ol hydrochloride was isolated as peak 1 after
neutralization and conversion of the free base to the hydrochloride
salt according to EXAMPLE 33, step 6. MS (ES) m/z 365
([M+H].sup.+); 98.4% ee.
Example 41
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)phenyl]pr-
opan-2-ol Hydrochloride
##STR00048##
[0872]
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy)ph-
enyl]propan-2-ol hydrochloride (EXAMPLE 40, step 1) was isolated as
peak 2 after neutralization and conversion of the free base to the
hydrochloride salt according to EXAMPLE 33, step 6. MS (ES) m/z 365
([M+H].sup.+); >99.9% ee.
Example 42
(1S,2R)-4-amino-1-(3-chlorophenyl)-1-(1H-indol-1-yl)butan-2-ol
Hydrochloride
##STR00049##
[0874] Step 1: A mixture of (2S,3S)-toluene-4-sulfonic acid
3-(3-chlorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester (EXAMPLE 33,
step 5, 1.9 g, 4.2 mmol) and sodium cyanide (0.23 g, 4.7 mmol) in
dry dimethylsulfoxide (20 mL) was heated at 100.degree. C.
(microwave). After 15 minutes, the cooled solution was taken up in
ethyl acetate (200 mL), washed with water (3.times.200 mL), dried
(sodium sulfate) and concentrated under vacuum to give a tan foam
(1.3 g) that was pre-adsorbed on silica gel (3 g). Flash column
chromatography (silica 30 g, 10%, 20%, 40% ethyl acetate/hexanes)
provided
(3R,4S)-4-(3-chlorophenyl)-3-hydroxy-4-indol-1-yl-butyronitrile
(1.2 g, 92%) as a tan foam. MS (ES) m/z 311 ([M+H].sup.+).
[0875] Step 2: A solution of
(3R,4S)-4-(3-chlorophenyl)-3-hydroxy-4-indol-1-yl-butyronitrile
(1.2 g, 3.9 mmol) in dry tetrahydrofuran (20 mL) was treated with
diborane-tetrahydrofuran solution (1.0 M, 20 mL, 20 mmol) at
23.degree. C. After 16 hours, the reaction was quenched with
methanol (7 mL) at 23.degree. C. and the solution was concentrated
under vacuum to give an off-white foam that was partitioned between
diethyl ether (200 mL) and a 1 N aqueous solution of sodium
hydroxide (200 mL). The organic phase was separated, washed with
brine (200 mL), dried (sodium sulfate) and concentrated under
vacuum to give a yellow foam (1.2 g) that was purified via Biotage
chromatography [Anal.ogix silica column, 2.times.40 g in series,
dichloromethane to 5% ammonia saturated methanol/dichloromethane]
to provide
(1S,2R)-4-amino-1-(3-chlorophenyl)-1-(1H-indol-1-yl)butan-2-ol
(0.43 g, 36%). The free base was converted to the hydrochloride
salt as described in EXAMPLE 33, step 6, to provide
(1S,2R)-4-amino-1-(3-chlorophenyl)-1-(1H-indol-1-yl)butan-2-ol
hydrochloride (0.47 g, 34%) as a foam. MS (ES) m/z 315
([M+H].sup.+).
Example 43
(1S,2R)-1-(3-bromophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00050##
[0877] Step 1: In an analogous manner to EXAMPLE 33, step 1,
(2E)-3-(3-bromophenyl)-acrylic acid ethyl ester was prepared from
diethyl ethoxycarbonylmethylphosphonate and 3-bromobenzaldehyde. MS
(ES) m/z 255 ([M+H].sup.+).
[0878] Step 2: In an analogous manner to EXAMPLE 33, step 2,
(2E)-3-(3-bromophenyl)prop-2-en-1-ol was prepared from
(2E)-3-(3-bromophenyl)-acrylic acid ethyl ester. MS (ES) m/z 195
([M+H-H.sub.2O].sup.+).
[0879] Step 3: In an analogous manner to EXAMPLE 117, step 4,
[(2R,3R)-3-(3-bromophenyl)oxiran-2-yl]methanol was prepared from
(2E)-3-(3-bromophenyl)prop-2-en-1-ol. MS (ES) m/z 211
([M+H-H.sub.2O].sup.+); 95% ee.
[0880] Step 4: In an analogous manner to EXAMPLE 33, step 4a
(Method B),
(2S,3S)-3-(3-bromophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol
was prepared from indoline and
[(2R,3R)-3-(3-bromophenyl)oxiran-2-yl]methanol. MS (ES) m/z 348
([M+H].sup.+).
[0881] Step 5: In an analogous manner to EXAMPLE 33, step 4b
(Method B),
(2S,3S)-3-(3-bromophenyl)-3-(1H-indol-1-yl)propane-1,2-diol was
prepared from
(2S,3S)-3-(3-bromophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-d-
iol. MS (ES) m/z 346 ([M+H].sup.+).
[0882] Step 6: In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-bromophenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared
from (2S,3S)-3-(3-bromophenyl)-3-(1H-indol-1-yl)propane-1,2-diol.
MS (ES) m/z 500 ([M+H].sup.+).
[0883] Step 7: In an analogous manner to EXAMPLE 33, step 6
(1S,2R)-1-(3-bromophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(3-bromophenyl)-2-hydroxy-3-indol-1-yl-propyl ester and
methylamine (2 N solution in methanol). MS (ES) m/z 359
([M+H].sup.+).
Example 44
3-[(1S,2R)-2-hydroxy-1-(1H-indol-1-yl)-3-(methylamino)propyl]benzonitrile
Hydrochloride
##STR00051##
[0885] A mixture of
(2S,3S)-3-(3-bromophenyl)-(1H-indol-1-yl)propane-1,2-diol (EXAMPLE
43, step 5, 1.4 g, 4.0 mmol), zinc (II) cyanide (4.7 g, 40 mmol)
and tetrakis(triphenylphosphine)palladium (0) (0.46 g, 0.40 mmol)
in de-gassed 1-methyl-2-pyrrolidinone (25 mL) was heated at
150.degree. C. in a sealed flask. After 3.5 hours, the cooled brown
mixture was diluted with ethyl acetate (250 mL) and filtered
through Celite. The filtrate was washed with water (5.times.250 mL)
and brine (1.times.250 mL), dried (sodium sulfate), and
concentrated under vacuum to give an amber oil (1.6 g) that was
pre-adsorbed on silica gel (6 g). Flash column chromatography
(silica 70 g, 30%, 60% ethyl acetate/hexanes) provided
3-[(1S,2S)-2,3-dihydroxy-1-(1H-indol-1-yl)propyl]benzonitrile (1.0
g, 83%) as a pale yellow foam. MS (ES) m/z 293 ([M+H].sup.+).
[0886] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-cyano-phenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared
from 3-[(1S,2S)-2,3-dihydroxy-1-(1H-indol-1-yl)propyl]benzonitrile.
MS (ES) m/z 447 ([M+H].sup.+).
[0887] In an analogous manner to EXAMPLE 33, step 6
3-[(1S,2R)-2-hydroxy-1-(1H-indol-1-yl)-3-(methylamino)propyl]benzonitrile
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(3-cyano-phenyl)-2-hydroxy-3-indol-1-yl-propyl ester and
methylamine (2 N solution in methanol). MS (ESI) m/z 306
([M+H].sup.+).
Example 45
(1SR,2RS)-3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-ph-
enylpropan-2-ol Hydrochloride
##STR00052##
[0889] Step 1: In an analogous manner to EXAMPLE 53, step
3,3-phenylglycidol was prepared from cinnamyl alcohol as a white
solid. MS (ES) m/z 151.1 ([M+H].sup.+).
[0890] Step 2: In an analogous manner to EXAMPLE 47, step 4,
(2SR,3SR)-3-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-3-phenylpropane-1,2-
-diol was prepared from
1-methyl-1,2,3,4-tetrahydroquinoxaline.sup.1 and 3-phenylglycidol
as a viscous colorless oil. MS (ES) m/z 299.0 ([M+H].sup.+); HRMS:
calcd for C.sub.18H.sub.22N.sub.2O.sub.2+H.sup.+, 299.1760; found
(ESI, [M+H].sup.+), 299.1739. .sup.1Cavagnol, J. C.; Wiselogle, F.
Y. J. Am. Chem. Soc. 1947, 69, 795-799.
[0891] Step 3: In an analogous manner to EXAMPLE 47, step 6,
(1SR,2RS)-3-(methylamino)-1-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1-p-
henylpropan-2-ol hydrochloride was prepared from
(2SR,3SR)-3-(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-3-phenylpropane-1,2-
-diol as a white powder. MS (ES) m/z 312.0 ([M+H].sup.+); HRMS:
calcd for C.sub.19H.sub.25N.sub.3O+H.sup.+, 312.2076; found (ESI,
[M+H].sup.+), 312.2065.
Example 46
(1SR,2RS)-3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinoxalin-1(2H)-yl]propan-2-ol Hydrochloride
##STR00053##
[0893] Compound
1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxaline was obtained
as a white powder side product of the reduction reaction of
quinoxaline to 1,2,3,4-tetrahydroquinoxaline using sodium
borohydride in trifluoroacetic acid..sup.2 MS (ES) m/z 217.1
([M+H].sup.+). .sup.2Bugle, R. C.; Osteryoung, R. A. J. Org. Chem.
1979, 44, 1719-1720.
[0894] In an analogous manner to EXAMPLE 47, step 4,
(2SR,3SR)-3-(4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-p-
henylpropane-1,2-diol was prepared from
1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxaline and
3-phenylglycidol (EXAMPLE 45, step 1) as a viscous colorless
oil.
[0895] In an analogous manner to EXAMPLE 47, step 6,
(1SR,2RS)-3-(methylamino)-1-phenyl-1-[4-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinoxalin-1(2H)-yl]propan-2-ol hydrochloride was prepared from
(2SR,3SR)-3-(4-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-p-
henylpropane-1,2-diol as a white powder. MS (ES) m/z 380.0
([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.24F.sub.3N.sub.3O+H.sup.+, 380.1950; found (ESI,
[M+H].sup.+), 380.1934.
Example 47
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00054##
[0897] Step 1: To a mixture of trans-3-fluorocinnamic acid (50 g,
300 mmol) and iodomethane (300 mL) in acetone (1 L) was added
portionwise cesium carbonate (147 g, 450 mmol, 1.5 equiv.), and the
mixture was heated at 65.degree. C. for 1.5 hours in a sealed
reaction vessel. Upon cooling to room temperature, the reaction
mixture was diluted with ethyl acetate (1 L), filtered through a
pad of silica gel, and concentrated to give 47.33 g (87%) of
trans-3-fluorocinnamic acid methyl ester as a colorless oil. MS
(ES) m/z 180.0 (M.sup.+).
[0898] Step 2: To a solution of trans-3-fluorocinnamic acid methyl
ester (69.61 g, 386 mmol) in dry dichloromethane (1 L) at
-78.degree. C. under nitrogen was added dropwise diisobutylaluminum
hydride (neat, 172 mL, 965 mmol, 2.5 equiv.) via an addition
funnel. After the addition was complete, the reaction mixture was
allowed to warm to -30.degree. C. and stirred for an additional 1
hour, then quenched with methanol (150 mL). Upon warming to room
temperature, the reaction mixture was treated with saturated
aqueous solution of sodium/potassium tartrate (300 mL) and stirred
for 30 minutes. The organic layer was washed sequentially with 1N
aqueous hydrochloric acid solution, saturated aqueous sodium
bicarbonate solution, brine, and dried (anhydrous sodium sulfate).
The crude oil was purified by silica gel chromatography (0-50%
ethyl acetate:hexane) to give 53.07 g (90%) of
trans-3-fluorocinnamyl alcohol as a colorless oil. MS (ES) m/z
152.1 (M.sup.+).
[0899] Step 3: An oven-dried, 3-neck, 2-L round bottom flask fitted
with two oven-dried addition funnels and a rubber septum was
charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30
equiv.), 4 A powdered, activated molecular sieves (40 g) and dry
dichloromethane (800 mL) under nitrogen. After being cooled to
-25.degree. C., to the reaction mixture was added titanium
isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) slowly via a hypodermic
syringe. After stirring for 10 minutes, anhydrous t-butyl
hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) was
added at a moderate rate via an addition funnel. The resulting
mixture was stirred at -25.degree. C. for 30 minutes.
trans-3-Fluorocinnamyl alcohol (25.0 g, 164 mmol) in dry
dichloromethane (50 mL) was added dropwise via an addition funnel
while maintaining the temperature at -25.degree. C. After the
addition, the reaction mixture was stirred at -25.degree. C. for 1
hour and at -20.degree. C. for another 3 hours. After the reaction
was complete, cooled aqueous sodium hydroxide solution (30%, 20 mL)
saturated with sodium chloride was added slowly at -20.degree. C.
After diethyl ether (150 mL) was added, the cold bath was removed
and the mixture was allowed to warm to .about.5.degree. C. and
stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added
and the mixture was stirred for 20 minutes, then filtered through a
pad of silica gel, and washed with ether (300 mL). The filtrate was
concentrated and toluene was used to azeotropically remove excess
t-butyl hydroperoxide. The residual oil was purified on silica gel
(0-30% ethyl acetate:hexane) to give 24.80 g (90%) of
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol as a viscous,
colorless oil. Percent ee: >96.5%. MS (ESI) m/z 169.1
([M+H].sup.+).
[0900] Step 4: A mixture of indoline (1.42 g, 11.89 mmol) and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (2.0 g, 11.89 mmol)
was heated at 125.degree. C. for 5 hours in a sealed reaction vial.
Upon cooling, the crude product was dissolved in ethyl acetate,
absorbed on Fluorocil, and purified by Biotage chromatography
(FlasH40i, silica, 0-55% EtOAc/hexane) to give 2.55 g (75%) of
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a colorless oil. MS (ESI) m/z 288.1 ([M+H].sup.+).
[0901] Step 5: A mixture of
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
(2.00 g, 6.96 mmol) and activated manganese dioxide (20.0 g, 230
mmol) in dichloromethane (30 mL) was stirred at 20.degree. C. for 3
hours. The mixture was diluted with ethyl acetate (15 mL), filtered
through a pad of silica gel, and concentrated. The crude product
was purified by Biotage chromatography (FlasH40i, silica, 0-70%
EtOAc/hexane) to give 1.40 g (71%) of
(2S,3S)-3-(3-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol as a
colorless oil. MS (ESI) m/z 286.0 ([M+H].sup.+). HRMS: calcd for
C.sub.17H.sub.16FNO.sub.2+H.sup.+, 286.1238; found (ESI,
[M+H].sup.+), 286.1239.
[0902] Step 6: To a solution of
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
(452 mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen was
added triethylamine (1.1 mL, 7.93 mmol). The mixture was cooled to
0.degree. C., and para-toluenesulfonyl chloride (423 mg, 2.22 mmol)
was added portionwise. The reaction mixture was stirred at
0.degree. C. for 1 hour and stored at 0.degree. C. overnight.
Methylamine in absolute ethanol (8 M, 5 mL, 40 mmol) was added and
the reaction mixture was sealed, and stirred overnight while
warming to room temperature. All volatiles were removed under
reduced pressure. The oil residue was dissolved in dichloromethane
(20 mL), washed with aqueous potassium carbonate (5 mL), dried
(anhydrous sodium sulfate), and concentrated. Purification by
Biotage chromatography (FlasH12i, silica, 0-15%
MeOH/dichloromethane/0.5% triethylamine) gave
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol,
which was dissolved dichloromethane (5 mL) and treated with a 1M
ethereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). To the
resulting solution was added hexane until white powder formed,
which was collected, washed with hexane, and dried in vacuo to
yield 209 mg (44%) of
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride as a white powder. MS (ES) m/z 299.0 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.19FN.sub.2O+H.sup.+, 299.1554; found
(ESI, [M+H].sup.+), 299.1553.
Example 48
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-methylphenyl)-1H-indol--
1-yl]propan-2-ol Hydrochloride
##STR00055##
[0904] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-methylphenyl]-1H-indol-1-yl}propane-1,-
2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 3-methylbenzeneboronic acid.
[0905] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(2-chlorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-methylphenyl]-1H-indol-1-yl}propane-1,-
2-diol.
[0906] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-methylphenyl)-1H-indol-
-1-yl]propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluoro-phenyl)-3-[3-(3-methylphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
389.2; HRMS: calcd for C25H25FN2O+H+, 389.20237; found (ESI,
[M+H]+), 389.2005.
Example 49
(1S,2R)-1-(4-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)propa-
n-2-ol Hydrochloride
##STR00056##
[0908] Step 1: In an analogous manner to EXAMPLE 47, step 3,
[(2R,3R)-3-(4-fluorophenyl)oxiran-2-yl]methanol was prepared from
trans-4-fluorocinnamyl alcohol.sup.3 as a white solid. Percent ee:
>97%. MS (ES) m/z 167.0 ([M-H].sup.-). .sup.3Takeuchi, R.; Ue,
N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am. Chem. Soc., 2001,
123, 9525-9534.
[0909] Step 2: In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(4-fluorophenyl)-3-(3-methyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 3-methylindole and
[(2R,3R)-3-(4-fluorophenyl)oxiran-2-yl]methanol as a viscous,
colorless oil. MS (ES) m/z 300.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.18FNO.sub.2+H.sup.+, 300.1400; found (ESI,
[M+H].sup.+), 300.1406.
[0910] Step 3: In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(4-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)prop-
an-2-ol Hydrochloride was prepared from
(2S,3S)-3-(4-fluorophenyl)-3-(3-methyl-1H-indol-1-yl)propane-1,2-diol
as a white powder. MS (ESI) m/z 313.1 ([M+H].sup.+); HRMS: calcd
for C.sub.19H.sub.21FN.sub.2O+H.sup.+, 313.1711; found (ESI,
[M+H].sup.+), 313.1727.
Example 50
(1S,2R)-1-(2-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00057##
[0912] In an analogous manner to EXAMPLE 47, step 1,
trans-2-fluorocinnamic acid methyl ester was prepared from
trans-2-fluorocinnamic acid as a white solid. MS m/z 180.9
([M+H].sup.+).
[0913] In an analogous manner to EXAMPLE 47, step 2,
trans-2-fluorocinnamyl alcohol was prepared from
trans-2-fluorocinnamic acid methyl ester as a colorless oil. MS
(ESI) m/z 152.0 [M].sup.+; HRMS: calcd for C.sub.9H.sub.9FO,
152.0637; found (ESI, [M].sup.+), 152.0640.
[0914] In an analogous manner to EXAMPLE 47, steps 3,
[(2R,3R)-3-(2-fluorophenyl)oxiran-2-yl]methanol was prepared from
trans-2-fluorocinnamyl alcohol as a white solid. MS m/z 169.0
([M+H].sup.+).
[0915] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(2-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol was
prepared from indole and
[(2R,3R)-3-(2-fluorophenyl)oxiran-2-yl]methanol as a viscous,
colorless oil. MS (ES) m/z 286.2 ([M+H].sup.+); HRMS: calcd for
C.sub.17H.sub.16FNO.sub.2+H.sup.+, 286.1238; found (ESI,
[M+H].sup.+), 286.1231.
[0916] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(2-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(2-fluorophenyl)-3-(3-methyl-1H-indol-1-yl)propane-1,2-diol
as a white powder. MS (ES) m/z 299.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19FN.sub.2O+H.sup.+, 299.1554; found (ESI,
[M+H].sup.+), 299.1557.
Example 51
(1S,2R)-1-(4-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00058##
[0918] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(4-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol was
prepared from indole and [3-(4-fluorophenyl)oxiran-2-yl]methanol
(EXAMPLE 49, step 1) as a viscous, colorless oil. MS (ES) m/z 286.1
([M+H].sup.+); HRMS: calcd for C.sub.17H.sub.16FNO.sub.2+H.sup.+,
286.1238; found (ESI, [M+H].sup.+), 286.1230.
[0919] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(4-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(4-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol as a
white powder. MS (ES) m/z 299.1 ([M+H].sup.+).
Example 52
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(3-methylphenyl)propan-2-ol
Hydrochloride
##STR00059##
[0921] In an analogous manner to EXAMPLE 47, step 1,
trans-3-methylcinnamic acid methyl ester was prepared from
trans-3-methylcinnamic acid.
[0922] In an analogous manner to EXAMPLE 47, step 2,
trans-3-methylcinnamyl alcohol was prepared from
trans-3-methylcinnamic acid methyl ester as a colorless oil.
[0923] In an analogous manner to EXAMPLE 47, steps 3,
[(2R,3R)-3-(3-methylphenyl)oxiran-2-yl]methanol was prepared from
trans-3-methylcinnamyl alcohol as a colorless oil. HRMS: calcd for
C.sub.10H.sub.12O.sub.2+H.sup.+, 165.0916; found (ESI,
[M+H].sup.+), 165.0926.
[0924] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(1H-indol-1-yl)-3-(3-methylphenyl)propane-1,2-diol was
prepared from indole and
[(2R,3R)-3-(3-methylphenyl)oxiran-2-yl]methanol as a viscous,
colorless liquid. MS (ES) m/z 282.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19NO.sub.2+H.sup.+, 282.1494; found (ESI,
[M+H].sup.+), 282.1488.
[0925] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(3-methylphenyl)propan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-(3-methylphenyl)propane-1,2-diol as a
white powder. MS (ES) m/z 295.3 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.20N.sub.2O+H.sup.+, 295.1805; found (ESI,
[M+H].sup.+), 295.1799.
Example 53
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol
Hydrochloride
##STR00060##
[0927] Step 1: In an analogous manner to EXAMPLE 47, step 1,
trans-2-methylcinnamic acid methyl ester was prepared from
trans-2-methylcinnamic acid.
[0928] Step 2: In an analogous manner to EXAMPLE 47, step 2,
trans-2-methylcinnamyl alcohol was prepared from
trans-2-methylcinnamic acid methyl ester as a colorless oil. MS
(ES) m/z 146.9 ([M-H].sup.-).
[0929] Step 3: To a solution of trans-2-methylcinnamyl alcohol
(1.50 g, 10.14 mmol) in dichloromethane (30 mL) was added sodium
carbonate (1.50 g, 14.19 mmol). The mixture was cooled to
10.degree. C. and peracetic acid (32 wt %, 2.56 mL, 12.16 mmol) was
added dropwise via an addition funnel. The reaction mixture was
stirred for 3 hours while warming to room temperature, and quenched
with saturated aqueous sodium sulfite solution (15 mL) slowly. More
dichloromethane (30 mL) was added and the mixture was extracted.
The organic layer was washed with brine, dried (anhydrous sodium
sulfate), and concentrated. The oil residue was purified by silica
gel chromatography (10-30% EtOAc/hexane) to give 920 mg (55%) of
3-(2-methylphenyl)glycidol as a colorless oil. HRMS: calcd for
C.sub.10H.sub.12O.sub.2+H.sup.+, 165.0916; found (ESI,
[M+H].sup.+), 165.0936.
[0930] Step 4: In an analogous manner to EXAMPLE 117, step 5,
(2SR,3SR)-3-(1H-indol-1-yl)-3-(2-methylphenyl)propane-1,2-diol was
prepared from indole and 3-(2-methylphenyl)glycidol as a viscous,
colorless liquid. MS (ES) m/z 282.2 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19NO.sub.2+H.sup.+, 282.1494; found (ESI,
[M+H].sup.+), 282.1499.
[0931] Step 5: In an analogous manner to EXAMPLE 47, step 6,
(1SR,2RS)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol
was prepared from
(2SR,3SR)-3-(1H-indol-1-yl)-3-(2-methylphenyl)propane-1,2-diol as
an oil.
[0932] Step 6: Racemic
(1SR,2RS)1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol
was dissolved in ethanol (20 mg/mL). The resulting solution was
stack injected onto the Supercritical Fluid Chromatography
instrument at 1 mL increments. The baseline resolved enantiomers,
using the conditions described below, were collected. The
enantiomeric purity of each enantiomer was determined under similar
Supercritical Fluid Chromatography conditions using a Chiralcel
OJ-H 5u, 250 mm L.times.4.6 mm ID column at 1.2 mL/minutes flow
rate using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del. USA). [0933] SFC Instrument: Berger
MultiGram Prep SFC (Berger Instruments, Inc. Newark, Del. 19702.
[0934] Column: Chiralcel OJ-H; 5u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc., Exton, Pa., USA) [0935] Column temperature:
35.degree. C. [0936] SFC Modifier: 15% MeOH with 1.0% DEA/85%
CO.sub.2 [0937] Flow rate: 50 mL/min [0938] Outlet Pressure: 100
bar [0939] Detector: UV at 220 nm
[0940] Step 7: In an analogous manner to EXAMPLE 144, step 2,
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol
hydrochloride was prepared as a white solid, from
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol,
which was isolated as Peak 1 of the chiral separation (step 6).
Chiral purity: 100%. MS (ESI) m/z 295.3 ([M+H].sup.+); HRMS: calcd
for C.sub.19H.sub.22N.sub.2O+H.sup.+, 295.1805; found (ESI,
[M+H].sup.+), 295.1795.
Example 54
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol
Hydrochloride
##STR00061##
[0942] In an analogous manner to EXAMPLE 53, step 7,
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol
hydrochloride was prepared as a white solid, from
(1R,2S)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-methylphenyl)propan-2-ol,
which was isolated as Peak 2 of the chiral separation (EXAMPLE 53,
step 6). Chiral purity: 100%. MS (ESI) m/z 295.3 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.22N.sub.2O+H.sup.+, 295.1805; found
(ESI, [M+H].sup.+), 295.1805.
Example 55
(1S,2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol
Hydrochloride
##STR00062##
[0944] Step 1: In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-methylbenzenesulfonate was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 47, step 5) as an ivory solid. HRMS: calcd for
C.sub.24H.sub.22FN.sub.2O.sub.4S+H.sup.+, 440.1326; found (ESI,
[M+H].sup.+), 440.1345.
[0945] Step 2:
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-methylbenzenesulfonate (200 mg, 0.456 mmol) was dissolved in a
solution of ethylamine in methanol (2.0 M, 10 mL) and stirred for
12 hours in a sealed reaction vessel. All volatiles were removed
under reduced pressure, and the liquid residue was dissolved in
dichloromethane (15 mL), washed with a saturated aqueous solution
of potassium carbonate, dried (anhydrous sodium sulfate), and
concentrated. Purification of the liquid residue by Biotage
chromatography (FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5%
triethylamine) gave
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(ethylamino)propan-2-ol,
which was used to prepare
(1S,2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol
hydrochloride as a white powder in an analogous matter to EXAMPLE
144, step 2. Yield: 99 mg (70%). MS (ES) m/z 313.1 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.21FN.sub.2O+H.sup.+, 313.1716; found
(ESI, [M+H].sup.+), 313.1716.
Example 56
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-morpholin-4-ylpropan-2-ol
Hydrochloride
##STR00063##
[0947] In an analogous manner to EXAMPLE 55, step 2,
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-morpholin-4-ylpropan-2-ol
hydrochloride was prepared from morpholine and
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-methylbenzenesulfonate (EXAMPLE 55, step 1) as a white powder. MS
(ES) m/z 355.1 ([M+H].sup.+); HRMS: calcd for
C.sub.21H.sub.23FN.sub.2O.sub.2+H.sup.+, 355.1816; found (ESI,
[M+H].sup.+), 355.1822.
Example 57
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(propylamino)propan-2-ol
Hydrochloride
##STR00064##
[0949] In an analogous manner to EXAMPLE 55, step 2,
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(propylamino)propan-2-ol
hydrochloride was prepared from propylamine and
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-methylbenzenesulfonate (EXAMPLE 55, step 1) as a white powder. MS
(ES) m/z 327.1 ([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.23FN.sub.2O+H.sup.+, 327.1867; found (ESI,
[M+H].sup.+), 327.1873.
Example 58
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)pro-
pan-2-ol Dihydrochloride
##STR00065##
[0951] In an analogous manner to EXAMPLE 55, step 2,
(1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)pr-
opan-2-ol dihydrochloride was prepared from 1-methylpiperazine and
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-methylbenzenesulfonate (EXAMPLE 55, step 1) as a white powder. MS
(ES) m/z 368.1 ([M+H].sup.+); HRMS: calcd for
C.sub.22H.sub.26FN.sub.3O+H.sup.+, 368.2133; found (ESI,
[M+H].sup.+), 368.2138.
Example 59
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(4-methylphenyl)propan-2-ol
Hydrochloride
##STR00066##
[0953] In an analogous manner to EXAMPLE 47, steps 3,
[(2R,3R)-3-(4-methylphenyl)oxiran-2-yl]methanol was prepared from
trans-4-methylcinnamyl alcohol.sup.3 as a colorless oil. MS (ES)
m/z 165.1 ([M+H].sup.+); HRMS: calcd for
C.sub.10H.sub.12O.sub.2+H.sup.+, 165.0916; found (ESI, [M+H]+),
165.0937.
[0954] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(1H-indol-1-yl)-3-(4-methylphenyl)propane-1,2-diol was
prepared from indole and
[(2R,3R)-3-(4-methylphenyl)oxiran-2-yl]methanol as a viscous
colorless liquid. MS (ES) m/z 282.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19NO.sub.2+H.sup.+, 282.1494; found (ESI,
[M+H].sup.+), 282.1492.
[0955] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(4-methylphenyl)propan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-(4-methylphenyl)propane-1,2-diol as a
white powder. MS (ES) m/z 295.1 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.22N.sub.2O+H.sup.+, 295.1805; found (ESI, [M+H]+),
295.1810.
Example 60
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)pr-
opan-2-ol Hydrochloride
##STR00067##
[0957] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)p-
ropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
(EXAMPLE 47, step 4) as a white solid. MS (ES) m/z 301.1
([M+H].sup.+); HRMS: calcdfor C.sub.18H.sub.21FN.sub.2O+H.sup.+,
301.1711;found (ESI, [M+H].sup.+), 301.1716.
Example 61
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00068##
[0959] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from indoline and [(2R,3R)-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m/z
270.2 ([M+H].sup.+); HRMS: calcd for
C.sub.17H.sub.20NO.sub.2+H.sup.+, 270.1494; found (ESI,
[M+H].sup.+), 270.1493.
[0960] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white solid. MS (ES) m/z 283.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.21N.sub.2O+H.sup.+, 283.1805; found (ESI,
[M+H].sup.+), 283.1810.
Example 63
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indo-
l-1-yl)propan-2-ol Hydrochloride
##STR00069##
[0962] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol was prepared from 2-methylindoline and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 302.1 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.20FNO.sub.2+H.sup.+, 302.1551; found
(ESI, [M+H].sup.+), 302.1556.
[0963] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol as a white solid. MS (ES) m/z 315.0 ([M+H].sup.+); HRMS:
calcd for C.sub.19H.sub.23FN.sub.2O+H.sup.+, 315.1867; found (ESI,
[M+H].sup.+), 315.1850.
Example 64
(1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophe-
nyl)-3-(methylamino)propan-2-ol Hydrochloride
##STR00070##
[0965] Step 1: A mixture of 7-fluoro-3,3-dimethyloxindole (EXAMPLE
99, step 5, 2.24 g 12.5 mmol) in toluene (15 mL) under nitrogen was
heated at 80.degree. C. Vitride (65 wt % in toluene, 6 mL, 19.3
mmol) was added dropwise via an addition funnel. The resulting
solution was stirred at 80.degree. C. for an additional 1.5 hours,
then cooled in an ice bath. Aqueous sodium hydroxide solution (1N,
15 mL) was added slowly to quench the reaction. Water (15 mL) was
added and the reaction mixture was extracted with ethyl acetate (20
mL). The organic layer was washed with brine, dried (anhydrous
sodium sulfate), filtered through a pad of silica gel, and
concentrated under reduced pressure to yield 1.68 g (82%) of
7-fluoro-3,3-dimethylindoline as a colorless oil. MS (ES) m/z 166.1
([M+H].sup.+); HRMS: calcd for C.sub.10H.sub.12FN+H.sup.+,
166.1032; found (ESI, [M+H].sup.+), 166.1040.
[0966] Step 2: In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluoroph-
enyl)propane-1,2-diol was prepared from
7-fluoro-3,3-dimethylindoline and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 334.1 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.21F.sub.2NO.sub.2+H.sup.+, 334.1613;
found (ESI, [M+H].sup.+), 334.1616.
[0967] Step 3: In an analogous mannerto EXAMPLE 47, step 6,
(1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluoroph-
enyl)-3-(methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluoroph-
enyl)propane-1,2-diol as a white solid. MS (ES) m/z 347
([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.24F.sub.2N.sub.2O+H.sup.+, 347.1929; found (ESI,
[M+H].sup.+), 347.1935.
Example 65
(1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamino-
)-1-phenylpropan-2-ol Hydrochloride
##STR00071##
[0969] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-phenylpropa-
ne-1,2-diol was prepared from 7-fluoro-3,3-dimethylindoline
(EXAMPLE 64, step 1) and [(2R,3R)-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m/z
316.1 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.22FNO.sub.2+H.sup.+, 316.1707; found (ESI,
[M+H].sup.+), 316.1690.
[0970] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamin-
o)-1-phenylpropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-phenylpropa-
ne-1,2-diol as a white solid. HRMS: calcd for
C.sub.20H.sub.25FN.sub.2O+H.sup.+, 329.2029; found (ESI,
[M+H].sup.+), 329.2041.
Example 66
(1S,2R)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indol-1-yl)-1-phenylpro-
pan-2-ol Hydrochloride
##STR00072##
[0972] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(7-methyl-2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-diol
was prepared from 7-methylindoline.sup.4 and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, colorless oil. MS (ES) m/z 284.2 ([M+H].sup.+); HRMS:
calcd for C.sub.18H.sub.21NO.sub.2+H.sup.+, 284.1651; found (ESI,
[M+H]+), 284.1650. .sup.4Gribble, G. W.; Hoffman, J. H. Synthesis
1977, 12, 859-860.
[0973] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indol-1-yl)-1-phenylpr-
opan-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-methyl-2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-diol
as a white solid. MS (ES) m/z 297.0 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.24N.sub.2O+H.sup.+, 297.1961; found (ESI,
[M+H].sup.+), 297.1957.
Example 67
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indo-
l-1-yl)propan-2-ol Hydrochloride
##STR00073##
[0975] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-(7-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol was prepared from 7-methylindoline.sup.4 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 302.1 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.20FNO.sub.2+H.sup.+, 302.1551; found
(ESI, [M+H].sup.+), 302.1551.
[0976] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(7-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol as a white solid. MS (ES) m/z 315.0 ([M+H].sup.+); HRMS:
calcd for C.sub.19H.sub.23FN.sub.2O+H.sup.+, 315.1873; found (ESI,
[M+H].sup.+), 315.1862.
Example 68
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indo-
l-1-yl)propan-2-ol Hydrochloride
##STR00074##
[0978] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-(5-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol was prepared from 5-methylindoline and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 302.1 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.20FNO.sub.2, 302.1551; found (ESI,
[M+H].sup.+), 302.1551.
[0979] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(5-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol as a white solid. MS (ES) m/z 315.0 ([M+H].sup.+); HRMS:
calcd for C.sub.19H.sub.23FN.sub.2O+H.sup.+, 315.1873; found (ESI,
[M+H].sup.+), 315.1896.
Example 69
(1S,2R)-1-(1H-indol-1-yl)-1-(3-methoxyphenyl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00075##
[0981] In an analogous manner to EXAMPLE 33, step 1, ethyl
(2E)-3-(3-methoxyphenyl)acrylate was prepared from
3-methoxybenzaldehyde and diethyl ethoxycarbonylmethylphosphonate.
.sup.1H NMR (DMSO): .quadrature.1.26 (t, 3H, OCH.sub.2CH.sub.3),
.quadrature.3.79 (s, 3H, OCH.sub.3), .quadrature.4.19 (q, 2H,
OCH.sub.2CH.sub.3), .quadrature.6.66 (d, 1H, CH.dbd.CHC(O)),
.quadrature.6.99 (m, 1H, CH.dbd.CH(CO)), .quadrature.7.31 (m, 3H,
ArH) and .quadrature.7.62 (d, 1H, ArH).
[0982] In an analogous manner to EXAMPLE 33, step 2,
(2E)-3-(3-methoxyphenyl)prop-2-en-1-ol was prepared from ethyl
(2E)-3-(3-methoxyphenyl)acrylate. MS (ES) m/z 147.2
([M+H-H.sub.2O].sup.+).
[0983] In analogous manner to EXAMPLE 117, step 4,
[(2R,3R)-3-(3-methoxyphenyl)oxiran-2-yl]methanol was prepared from
(2E)-3-(3-methoxyphenyl)prop-2-en-1-ol. MS (ES) m/z 222
([M+H+CH.sub.3CN].sup.+); 93.2% ee.
[0984] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(1H-indol-1-yl)-3-(3-methoxyphenyl)propane-1,2-diol was
prepared from 1H-indole and
[(2R,3R)-3-(3-methoxyphenyl)oxiran-2-yl]methanol. MS (ES) m/z 298.2
([M+H].sup.+).
[0985] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-(1H-indol-1-yl)-3-(3-methoxyphenyl)-propyl ester was
prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-(3-methoxyphenyl)propane-1,2-diol. MS
(ES) m/z 452.2 ([M+H].sup.+).
[0986] In an analogous manner to EXAMPLE 33, step 6
(1S,2R)-1-(1H-indol-1-yl)-1-(3-methoxyphenyl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-(1H-indol-1-yl)-3-(3-methoxyphenyl)-propyl ester. MS
(ES) m/z 311.3 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.22N.sub.2O.sub.2+H+, 311.17540; found (ESI,
[M+H].sup.+), 311.1758.
Example 70
(1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00076##
[0988] A mixture of methyl trans-3-(4-methoxyphenyl)glycidate (2.11
g, 10.1 mmol) and indoline (1.14 mL, 10.1 mmol) was heated to
135.degree. C. in a sealed tube for 16 hours. The cooled reaction
mixture was then directly purified by flash chromatography (silica,
20%, 30% ethyl acetate/hexane) to yield 2.94 g (89%) of methyl
(2SR,3SR)-3-(2,3-dihydro-1H-indol-1-yl)-2-hydroxy-3-(4-methoxyphenyl)
propanoate as a yellow solid. MS (ES) m/z 328.2 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.21NO.sub.4+H.sup.+, 328.15434; found
(ESI, [M+H].sup.+), 328.1536.
[0989] To a solution of methyl
(2SR,3SR)-3-(2,3-dihydro-1H-indol-1-yl)-2-hydroxy-3-(4-methoxyphenyl)prop-
anoate (2.63 g, 8.0 mmol) in anhydrous toluene (50 mL) at 0.degree.
C. under nitrogen was added a solution of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.87 g, 8.2 mmol) in
anhydrous toluene (50 mL) over 5 minutes. The reaction mixture was
stirred 0.degree. C. to room temperature for 1.5 hours then
quenched by the addition of 7% w/v aqueous sodium carbonate
solution (100 mL). The resulting biphasic mixture was stirred
vigorously for 5 minutes then partitioned between ethyl acetate
(300 mL) and 7% w/v aqueous sodium carbonate (250 mL). The organic
phase was separated, washed with 7% w/v aqueous sodium carbonate
solution (3.times.250 mL), water (250 mL) and saturated brine (250
mL), dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure to give a lilac solid.
Purification by flash chromatography (silica, 20%, 30% ethyl
acetate/hexane) afforded 2.5 g (96%) of methyl
(2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)propanoate
as a cream solid. MS (ES) m/z 326.3 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.19NO.sub.4+H.sup.+, 326.13869; found (ESI,
[M+H].sup.+), 326.1378.
[0990] A solution of methyl
(2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)propanoate
(2.43 g, 7.5 mmol) in methylamine solution (33% wt. in absolute
ethanol, 40 mL) was heated to 75.degree. C. in a sealed tube for 1
hour. The cooled reaction mixture was then concentrated under
reduced pressure to afford a yellow syrup. Purification by
crystallization from 80% chloroform/hexane (50 mL) afforded 1.93 g
(80%) of
(2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)-N-methylpropana-
mide as a white crystalline solid. MS (ES) m/z 323.2 ([M-H].sup.-);
HRMS: calcd for C.sub.19H.sub.20N.sub.2O.sub.3+H.sup.+, 325.15467;
found (ESI, [M+H].sup.+), 325.1562.
[0991] To a solution of
(2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)-N-methylpropana-
mide (900 mg, 2.8 mmol) in anhydrous tetrahydrofuran (50 mL) at
room temperature under nitrogen was added dropwise a solution of
borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 13.9 mL,
13.9 mmol) and the mixture heated to reflux for 3 hours. The
reaction mixture was then cooled to 50.degree. C., methanol (20 mL)
was added, and the mixture stirred at 50.degree. C. for 1 hour. The
cooled reaction mixture was then concentrated under reduced
pressure to afford a white solid. Purification by flash
chromatography (silica, 15% methanol/dichloromethane) afforded 272
mg (32%). of
(1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-o-
l as a yellow syrup. The product was dissolved in absolute ethanol
(4 mL), a solution of hydrogen chloride (4 M in 1,4-dioxane, 0.28
mL, 1.12 mmol) added, the solution stirred for 10 minutes then
concentrated under reduced pressure to afford a white foam.
Crystallization from 1:1:1 v/v absolute ethanol:diethyl ether:
hexane (12 mL) at -35.degree. C. afforded 81.3 mg (8%) of
(1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-o-
l hydrochloride as a hygroscopic white solid. MS (ES) m/z 311.3
([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.22N.sub.2O.sub.2+H.sup.+, 311.17540; found (ESI,
[M+H].sup.+), 311.176.
Example 71
(1RS,2SR)-3-(methylamino)-1-(2-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00077##
[0993] Step 1: A mixture of sodium hydride (60% in mineral oil,
0.40 g, 10 mmol) and tert-butanol (5 mL) was stirred for 15 minutes
under nitrogen at room temperature. 2-Methylindole (1.31 g, 10
mmol) in methylene chloride (2 mL) was then added and the mixture
was stirred for an additional 30 minutes. at room temperature. A
pre-mixed solution of titanium isopropoxide (3.55 mL, 12 mmol) and
trans-3-phenylglycidol (1.5 g, 10 mmol) in methylene chloride (2
mL) was added, and the reaction mixture was stirred at room
temperature for 15 hours until no epoxide remained as determined by
tic. The mixture was filtered through a Celite pad, and the
filtrate was then treated with a 2N aqueous solution of
hydrochloric acid (50 mL) with stirring over 30 minutes. The
organic layer was separated and the aqueous layer was extracted
with methylene chloride several times. The combined extracts were
washed with water, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was purified via
Biotage Horizon (Flash 40 M, silica, gradient from 10% ethyl
acetate/hexane to 65% ethyl acetate/hexane) to yield
(2RS,3RS)-3-(2-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol as a
white solid. MS (ESI) m/z 282 ([M+H].sup.+).
[0994] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(2-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(2-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol as an
oil. MS (ESI) m/z 436 ([M+H].sup.+).
[0995] In an analogous mannerto EXAMPLE 5,
(1RS,2SR)-3-(methylamino)-1-(2-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(2-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol) as a tan solid. MS (ES) m/z
295.0; HRMS: calcd for C19H22N2O+H+, 295.18049; found (ESI,
[M+H].sup.+), 295.1818.
Example 72
(1RS,2SR)-1-(1H-benzimidazol-1-yl)-3-(methylamino)-1-phenyl
propan-2-ol Hydrochloride
##STR00078##
[0997] In an analogous manner to EXAMPLE 17, step 1
(2RS,3RS)-3-(1H-benzimidazol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from benzimidazole and trans-3-phenylglycidol as an oily
solid. MS (ESI) m/z 269 ([M+H].sup.+).
[0998] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-benzoimidazol-1-yl-2-hydroxy-3-phenyl-propyl ester was prepared
from (2RS,3RS)-1-(1H-benzimidazol-1-yl)-3-phenyl-propane-1,2-diol
as a white solid. MS (ESI) m/z 423 ([M+H].sup.+).
[0999] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-1-(1H-benzimidazo-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-benzoimidazol-1-yl-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol) as a white solid. MS (ES) m/z
282.1; HRMS: calcd for C17H19N3O+H+, 282.16009; found (ESI,
[M+H].sup.+), 282.1617.
Example 73
(1RS,2SR)-3-(methylamino)-1-(2-methyl-1H-benzimidazol-1-yl)-1-phenylpropan-
-2-ol Hydrochloride
##STR00079##
[1001] In an analogous manner to EXAMPLE 17, step 1
(2RS,3RS)-3-(2-methyl-1H-benzimidazol-1-yl)-3-phenyl-propane-1,2-diol
was prepared from 2-methylbenzimidazole and trans-3-phenylglycidol
as a yellow solid. MS (ESI) m/z 283 ([M+H].sup.+).
[1002] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-(2-methyl-benzoimidazol-1-yl)-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(2-methyl-1H-benzimidazol-1-yl)-3-phenyl-propane-1,2-diol
as a white solid. MS (ESI) m/z 437 ([M+H].sup.+).
[1003] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-1-(2-methyl-1H-benzimidazo-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic
acid 2-hydroxy-3-(2-methyl-benzoimidazol-1-yl)-3-phenyl-propyl
ester and methylamine as a white solid. MS (ES) m/z 296.1; SHRMS:
calcd for C18H21N3O+H+, 296.17574; found (ESI, [M+H].sup.+),
296.1752.
Example 74
(1RS,2SR)-1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenyl
propan-2-ol Hydrochloride
##STR00080##
[1005] In an analogous manner to EXAMPLE 17, step 1
(2RS,3RS)-3-(4-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 4-methoxyindole and trans-3-phenylglycidol as an oil.
MS (ESI) m/z 298 ([M+H].sup.+).
[1006] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-(4-methoxy-indol-1-yl)-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(4-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as
a white solid. MS (ESI) m/z 452 ([M+H].sup.+).
[1007] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-3-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
2-hydroxy-3-(4-methoxy-indol-1-yl)-3-phenyl-propyl ester and
methylamine as a white solid. MS (ESI) m/z 311; HRMS: calcd for
C19H22N2O2+H+, 311.17540; found (ESI, [M+H].sup.+), 311.1772
Example 75
(1S,2R)-1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00081##
[1009] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(5-fluoro-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 5-fluoroindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 286 ([M+H].sup.+).
[1010] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(5-fluoro-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as an
oil. MS (ESI) m/z 438 ([M+H].sup.+).
[1011] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(5-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a white solid. MS (ES) m/z 299.1; HRMS: calcd for
C18H19FN2O+H+, 299.15542; found (ESI, [M+H].sup.+), 299.1556.
Example 76
(1S,2R)-1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00082##
[1013] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(5-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 5-methoxyindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 298 ([M+H].sup.+).
[1014] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(5-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(5-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as an
oil. MS (ESI) m/z 452 ([M+H].sup.+).
[1015] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(5-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a white solid. MS (ES) m/z 311.1; HRMS: calcd for
C19H22N2O2+H+, 311.17540; found (ESI, [M+H].sup.+), 311.1745.
Example 77
(1S,2R)-1-(7-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00083##
[1017] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(7-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 7-methoxyindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 298 ([M+H].sup.+).
[1018] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(7-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(7-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as an
oil. MS (ESI) m/z 452 ([M+H].sup.+).
[1019] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(7-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(7-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a white solid. MS (ES) m/z 311.1; HRMS: calcd for
C19H22N2O2+H+, 311.17540; found (ESI, [M+H].sup.+), 311.1753.
Example 78
(1S,2R)-1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenyl
propan-2-ol Hydrochloride
##STR00084##
[1021] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(4-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 4-methoxyindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 298 ([M+H].sup.+).
[1022] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(4-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(4-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as an
oil. MS (ESI) m/z 452 ([M+H].sup.+).
[1023] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(4-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(4-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a white solid. MS (ESI) m/z 311; HRMS: calcd for
C19H22N2O2+H+, 311.17540; found (ESI, [M+H].sup.+), 311.175.
Example 79
(1S,2R)-1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenyl
propan-2-ol Hydrochloride
##STR00085##
[1025] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(6-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 6-methoxyindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 298 ([M+H].sup.+).
[1026] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(6-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(6-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as an
oil. MS (ESI) m/z 452 ([M+H].sup.+).
[1027] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(6-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a white solid. MS (ESI) m/z 311; HRMS: calcd for
C19H22N2O2+H+, 311.17540; found (ESI, [M+H].sup.+), 311.1757.
Example 80
(1RS,2SR)-1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenyl
propan-2-ol Hydrochloride
##STR00086##
[1029] In an analogous manner to EXAMPLE 17, step 1
(2RS,3RS)-3-(5-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 5-methoxyindole and trans-3-phenylglycidol as an oil.
MS (ESI) m/z 298 ([M+H].sup.+).
[1030] In an analogous manner to EXAMPLE 1, step 2
(2RS,3RS)-toluene-4-sulfonic acid
3-(5-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2RS,3RS)-3-(5-methoxy-1H-indol-1-yl)-3-phenyl-propane-1,2-diol as
an oil. MS (ESI) m/z 452 ([M+H].sup.+).
[1031] In an analogous manner to EXAMPLE 5,
(1RS,2SR)-1-(5-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid
3-(5-methoxy-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a white solid. MS (ESI) m/z 311; HRMS: calcd for
C19H22N2O2+H+, 311.17540; found (ESI, [M+H].sup.+), 311.1756.
Example 81
(1S,2R)-1-(3-fluorophenyl)-1-(6-methoxy-1H-indol-1-yl)-3-(methyl-amino)pro-
pan-2-ol Hydrochloride
##STR00087##
[1033] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(6-methoxy-1H-indol-1-yl)-3-(3-fluorophenyl)-propane-1,2-diol
was prepared from 6-methoxyindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as an oil. MS (ESI) m/z 316 ([M+H].sup.+).
[1034] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(6-methoxy-indol-1-yl)-2-hydroxy-3-(3-fluorophenyl)-propyl ester
was prepared from
(2S,3S)-3-(6-methoxy-1H-indol-1-yl)-3-(3-fluorophenyl)-propane-1,2-diol
as an oil. MS (ESI) m/z 470 ([M+H].sup.+).
[1035] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)-1--
phenylpropan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(6-methoxy-indol-1-yl)-2-hydroxy-3-(3-fluorophenyl)-propyl ester
and methylamine as a white solid. MS (ES) m/z 329.2; HRMS: calcd
for C19H21FN2O2+H+, 329.16598; found (ESI, [M+H].sup.+),
329.1663.
Example 82
(1S,2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-
-ol
##STR00088##
[1037] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)propane-1,2-diol
was prepared from 7-azaindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid. MS (ES) m/z 269.2; HRMS: calcd for C16H16N2O2+H+,
269.12845; found (ESI, [M+H].sup.+), 269.13.
[1038] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-phenyl-3-pyrrolo[2,3-b]pyridin-1-yl-propyl ester was
prepared from
(2S,3S)-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)propane-1,2-diol
as an oil. MS (ESI) m/z 423 ([M+H].sup.+).
[1039] In an analogous manner to EXAMPLE 5,
(1S,2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-1-yl)propan--
2-ol was prepared from (2S,3S)-toluene-4-sulfonic acid
2-hydroxy-3-phenyl-3-pyrrolo[2,3-b]pyridin-1-yl-propyl ester and
methylamine as a white solid. MS (ES) m/z 282.3; HRMS: calcd for
C17H19N3O+H+, 282.16009; found (ESI, [M+H].sup.+), 282.16.
Example 83
(1S,2R)-1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methy-
lamino)propan-2-ol Hydrochloride
##STR00089##
[1041] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane--
1,2-diol was prepared from 5-chloroindoline and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 322.1 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.17ClFNO.sub.2+H.sup.+, 322.1005;
found (ESI, [M+H].sup.+), 322.1005.
[1042] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(meth-
ylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane--
1,2-diol as a white solid. MS (ES) m/z 335.1 ([M+H].sup.+); HRMS:
calcd for C.sub.18H.sub.20ClFN.sub.2O+H.sup.+, 335.1326; found
(ESI, [M+H].sup.+), 335.1349.
Example 84
(1S,2R)-3-methylamino-1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-1-yl)propan-2-o-
l Dihydrochloride
##STR00090##
[1044] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(7-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)-3-phenylpropane-1,2-di-
ol was prepared from 7-chloro-1H-pyrrolo[2,3-c]pyridine.sup.5 and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ES) m/z 303 ([M+H].sup.+). .sup.5Zhang, Z., et al., J.
Org. Chem. 2002, 67, 2345-2347
[1045] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-2-hydroxy-3-phenyl-propyl
ester was prepared from
(2S,3S)-3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-3-phenyl-propane-1,2-diol
as an oil. MS (ESI) m/z 457 ([M+H].sup.+).
[1046] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(7-chloro-pyrrolo[2,3-c]pyridine-1-yl)-3-methylamino-1-phenyl-p-
ropan-2-ol was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-2-hydroxy-3-phenyl-propyl
ester and methylamine as a white solid. MS (ES) m/z 316.1
([M+H].sup.+).
[1047] Step 4:
(1S,2R)-1-(7-chloro-pyrrolo[2,3-c]pyridine-1-yl)-3-methylamino-1-phenyl-p-
ropan-2-ol (0.12 g, 0.38 mmol) was dissolved in ethanol (20 mL) and
treated with 10% palladium on carbon. The reaction mixture placed
under 50 psi of hydrogen on a Parr shaker for 15 hours. The
reaction mixture was filtered through a Celite pad and the filtrate
was concentrated in vacuo. The crude product was purified via
Biotage Horizon (Flash 25S, silica, gradient from 30% to 100% of
0.9% ammonium hydroxide in 10% methanol-methylene
chloride/methylene chloride) to give a white solid as the free base
of the expected product. The free base was dissolved in a minimum
amount of ethanol and treated with a 1N ethereal solution of
hydrochloric acid until the solution was pH=3 followed by diethyl
ether. The product was then crystallized by adding a minimum amount
of ethyl acetate to afford the titled compound,
(1S,2R)-3-methylamino-1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-1-yl)-propan-2-
-ol dihydrochloride as a white solid. MS (ES) m/z 282.1.
Example 85
(1S,2R)-1-(5-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methyl-amino)prop-
an-2-ol Hydrochloride
##STR00091##
[1049] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(5-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)-propane-1,2-diol
was prepared from 5-fluoroindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as an oil. MS (ESI) m/z 304 ([M+H].sup.+).
[1050] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(5-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)-propane-1,2-diol
as an oil. MS (ESI) m/z 458 ([M+H].sup.+).
[1051] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(5-fluoro-1H-indol-3-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic
acid 3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine as a light tan solid. MS (ES) m/z 317.2; HRMS: calcd
for C18H18F2N20+H+, 317.14599; found (ESI, [M+H].sup.+),
317.1472.
Example 86
(1S,2R)-3-methylamino-1-(3-fluorophenyl)-1-(1H-pyrrolo[2,3-c]pyridin-1-yl)
propan-2-ol Dihydrochloride
##STR00092##
[1053] In an analogous manner to EXAMPLE 17, step 1
(2S,3S)-3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-3-(3-fluorophenyl)-propan-
e-1,2-diol was prepared from
7-chloro-1H-pyrrolo[2,3-c]pyridine.sup.5 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as an oil. MS (ESI) m/z 321 ([M+H].sup.+).
[1054] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-2-hydroxy-3-(3-fluorophenyl)-prop-
yl ester was prepared from
(2S,3S)-3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-3-(3-fluorophenyl)-propan-
e-1,2-diol as an oil. MS (ESI) m/z 475 ([M+H].sup.+).
[1055] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(7-chloro-pyrrolo[2,3-c]pyridine-1-yl)-3-methylamino-1-(3-fluor-
ophenyl)-propan-2-ol was prepared from (2S,3S)-toluene-4-sulfonic
acid
3-(7-chloro-pyrrolo[2,3-c]pyridin-1-yl)-2-hydroxy-3-(3-fluorophenyl)-prop-
yl ester and methylamine as a white solid. MS (ESI) m/z 334
([M+H].sup.+).
[1056] In an analogous mannerto EXAMPLE 84, step 4
(1S,2R)-3-methylamino-1-(3-fluorophenyl)-1-(1H-pyrrolo[2,3-c]pyridin-1-yl-
)-propan-2-ol dihydrochloride was prepared from
(1S,2R)-1-(7-chloro-pyrrolo[2,3-c]pyridine-1-yl)-3-methylamino-1-(3-fluor-
ophenyl)-propan-2-ol as a white solid. MS (ESI) m/z 282.1
([M+H].sup.+).
Example 87
(1S,2R)-1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpro-
pan-2-ol Hydrochloride
##STR00093##
[1058] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-diol
was prepared from 5-chloroindoline and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, colorless oil. MS (ES) m/z 304.1 ([M+H].sup.+); HRMS:
calcd for C.sub.17H.sub.18ClNO.sub.2+H.sup.+, 304.1099; found (ESI,
[M+H].sup.+), 304.1081.
[1059] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phenylpr-
opan-2-ol hydrochloride was prepared from
2S,3S)-3-(5-chloro-2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-diol
as a white powder. MS (ES) m/z 317.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.21ClN.sub.2O+H.sup.+, 317.1421; found (ESI,
[M+H].sup.+), 317.1431.
Example 88
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluorophe-
nyl)-3-(methylamino)propan-2-ol Hydrochloride
##STR00094##
[1061] Step 1: In an analogous manner to EXAMPLE 165, step
1,6-chloro-3,4-dihydro-2H-1,4-benzoxazine was prepared from
6-chloro-2H-1,4-benzoxazin-3(4H)-one as a yellow solid. MS (ES) m/z
170.0 ([M+H].sup.+); HRMS: calcd for C.sub.8H.sub.8ClNO+H.sup.+,
170.0367; found (ESI, [M+H].sup.+), 170.0365.
[1062] Step 2: In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3,5-difluoroph-
enyl)propane-1,2-diol was prepared from
6-chloro-3,4-dihydro-2H-1,4-benzoxazine and
[(2R,3R)-3-(3,5-difluorophenyl)oxiran-2-yl]methanol (EXAMPLE 157,
step 3) as a viscous, yellowish liquid. MS (ES) m/z 356.1
([M+H].sup.+); HRMS: calcd for
C.sub.17H.sub.16ClF.sub.2NO.sub.3+H.sup.+, 356.0860; found (ESI,
[M+H].sup.+), 356.0869.
[1063] Step 3: In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluoroph-
enyl)-3-(methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3,5-difluoroph-
enyl)propane-1,2-diol as a white powder. MS (ES) m/z 369.1
([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19ClF.sub.2N.sub.2O.sub.2+H.sup.+, 369.1176; found
(ESI, [M+H].sup.+), 369.1178.
Example 89
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4--
benzoxazin-4-yl)propan-2-ol Hydrochloride
##STR00095##
[1065] In an analogous manner to EXAMPLE 165, step
1,2-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from
2-methyl-2H-1,4-benzoxazin-3(4H)-one.sup.6 as a brown oil. MS (ES)
m/z 149.9 ([M+H].sup.+). .sup.6Wheeler, K. W. J. Med. Pharm. Chem.
1962, 5, 1378-1383.
[1066] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl-
)propane-1,2-diol was prepared from
2-methyl-3,4-dihydro-2H-1,4-benzoxazine and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, brown liquid. MS (ES) m/z 318.2 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.20FNO.sub.3+H.sup.+, 318.1500; found
(ESI, [M+H].sup.+), 318.1513.
[1067] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-
-benzoxazin-4-yl)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl-
)propane-1,2-diol as a white powder. MS (ES) m/z 331.0
([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.23FN.sub.2O.sub.2+H.sup.+, 331.1816; found (ESI,
[M+H].sup.+), 331.1804.
Example 90
(1S,2R)-3-(methylamino)-1-(6-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00096##
[1069] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(6-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 6-methylindole and 2R,3R-(+)-3-phenylglycidol as an
oil. MS (ESI) m/z 282 ([M+H].sup.+).
[1070] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(6-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(6-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol MS
(ESI) m/z 436 ([M+H].sup.+).
[1071] In an analogous manner to EXAMPLE 5
(1S,2R)-3-(methylamino)-1-(6-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(6-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol); MS (ESI) m/z 295
([M+H].sup.+); HRMS: calcd for C19H22N2O+H+, 295.18049; found
(ESI-FT/MS, [M+H]1+), 295.1809.
Example 91
(1S,2R)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00097##
[1073] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(7-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 7-methylindole and 2R,3R-(+)-3-phenylglycidol as an
oil. MS (ESI) m/z 282 ([M+H].sup.+).
[1074] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(7-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(7-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol MS
(ESI) m/z 436 ([M+H].sup.+).
[1075] In an analogous manner to EXAMPLE 5
(1S,2R)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(7-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol); MS (ESI) m/z 295
([M+H].sup.+); HRMS: calcd for C19H22N2O+H+, 295.18049; found
(ESI-FT/MS, [M+H]1+), 295.1809.
Example 92
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)prop-
an-2-ol Hydrochloride
##STR00098##
[1077] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-fluorophenyl)-3-(5-methyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 5-methylindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (see EXAMPLE 47,
step 3) as an oil. MS (ESI) m/z 300 ([M+H].sup.+).
[1078] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-(5-methyl-indol-1-yl)-2-hydroxy-propyl ester
was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(5-methyl-1H-indol-1-yl)propane-1,2-diol
MS (ESI) m/z 454 ([M+H].sup.+).
[1079] In an analogous manner to EXAMPLE 5
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)pro-
pan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic
acid 3-(3-fluorophenyl)-3-(5-methyl-indol-1-yl)-2-hydroxy-propyl
ester and methylamine (2N solution in methanol); MS (ESI) m/z 313
([M+H].sup.+); HRMS: calcd for C19H21FN2O+H+, 313.17107; found
(ESI-FTMS, [M+H]1+), 313.17163.
Example 93
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)prop-
an-2-ol Hydrochloride
##STR00099##
[1081] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-fluorophenyl)-3-(7-methyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 7-methylindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (see EXAMPLE 47,
step 3) as an oil. MS (ESI) m/z 300 ([M+H].sup.+).
[1082] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-(7-methyl-indol-1-yl)-2-hydroxy-propyl ester
was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(7-methyl-1H-indol-1-yl)propane-1,2-diol
MS (ESI) m/z 454 ([M+H].sup.+).
[1083] In an analogous manner to EXAMPLE 5
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-1H-indol-1-yl)pro-
pan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic
acid 3-(3-fluorophenyl)-3-(7-methyl-indol-1-yl)-2-hydroxy-propyl
ester and methylamine (2N solution in methanol); MS (ESI) m/z 313
([M+H].sup.+); HRMS: calcd for C19H21FN2O+H+, 313.17107; found
(ESI-FTMS, [M+H]1+), 313.17141.
Example 94
(1S,2R)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00100##
[1085] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(4-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 4-methylindole.sup.7 and 2R,3R-(+)-3-phenylglycidol
as an oil. MS (ESI) m/z 282 ([M+H].sup.+). .sup.7 Raucher, Stanley;
Koolpe, Gary A. J. Org. Chem. 1983, 48(12), 2066-9
[1086] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(4-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(4-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol MS
(ESI) m/z 436 ([M+H].sup.+).
[1087] In an analogous manner to EXAMPLE 5
(1S,2R)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(4-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol); MS (ESI) m/z 295
([M+H].sup.+); HRMS: calcd for C19H22N2O+H+, 295.18049; found
(ESI-FT/MS, [M+H]1+), 295.1811.
Example 95
(1S,2R)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00101##
[1089] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(5-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 5-methylindole and 2R,3R-(+)-3-phenylglycidol as an
oil. MS (ESI) m/z 282 ([M+H].sup.+).
[1090] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(5-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester was
prepared from
(2S,3S)-3-(5-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol MS
(ESI) m/z 436 ([M+H].sup.+).
[1091] In an analogous manner to EXAMPLE 5
(1S,2R)-3-(methylamino)-1-(5-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid
3-(5-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and
methylamine (2N solution in methanol); MS (ESI) m/z 295
([M+H].sup.+); HRMS: calcd for C19H22N2O+H+, 295.18049; found
(ESI-FT/MS, [M+H]1+), 295.1812.
Example 96
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)prop-
an-2-ol Hydrochloride
##STR00102##
[1093] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-fluorophenyl)-3-(4-methyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 4-methylindole.sup.7 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (see EXAMPLE 47,
step 3) as an oil. MS (ESI) m/z 300 ([M+H].sup.+).
[1094] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-(4-methyl-indol-1-yl)-2-hydroxy-propyl ester
was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(4-methyl-1H-indol-1-yl)propane-1,2-diol
MS (ESI) m/z 454 ([M+H].sup.+).
[1095] In an analogous manner to EXAMPLE 5
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-methyl-1H-indol-1-yl)pro-
pan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic
acid 3-(3-fluorophenyl)-3-(4-methyl-indol-1-yl)-2-hydroxy-propyl
ester and methylamine (2N solution in methanol); MS (ESI) m/z 313
([M+H].sup.+); HRMS: calcd for C19H21FN2O+H+, 313.17107; found
(ESI-FT/MS, [M+H]1+), 313.171.
Example 97
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-ethyl-1H-indol-1-yl)propa-
n-2-ol Hydrochloride
##STR00103##
[1097] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-fluorophenyl)-3-(3-ethyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 3-ethylindole.sup.8 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (see EXAMPLE 47,
step 3) as an oil. MS (ESI) m/z 314 ([M+H].sup.+). .sup.8Ainsworth,
D. P.; Suschitzky, Hans J. Chem. Soc. [Section] C: Organic 1967,
(4), 315-19
[1098] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-(3-ethyl-indol-1-yl)-2-hydroxy-propyl ester
was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-ethyl-1H-indol-1-yl)propane-1,2-diol
MS (ESI) m/z 468 ([M+H].sup.+).
[1099] In an analogous manner to EXAMPLE 5
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-ethyl-1H-indol-1-yl)prop-
an-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic
acid 3-(3-fluorophenyl)-3-(3-ethyl-indol-1-yl)-2-hydroxy-propyl
ester and methylamine (2N solution in methanol); MS (ESI) m/z 327
([M+H].sup.+); HRMS: calcd for C20H23FN2O+H+, 327.18672; found
(ESI, [M+H]+), 327.1871.
Example 98
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indol-1-yl)prop-
an-2-ol Hydrochloride
##STR00104##
[1101] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-fluorophenyl)-3-(3-phenyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 3-phenylindole.sup.9 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (see EXAMPLE 47,
step 3) as an oil; MS (ESI) m/z 362 ([M+H].sup.+). .sup.9Cacchi,
Sandro; Fabrizi, Giancarlo; Marinelli, Fabio; Moro, Leonardo; Pace,
Paola Synlett 1997, (12), 1363-1366.
[1102] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-(3-phenyl-indol-1-yl)-2-hydroxy-propyl ester
was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-phenyl-1H-indol-1-yl)propane-1,2-diol
MS (ESI) m/z 516 ([M+H].sup.+).
[1103] In an analogous manner to EXAMPLE 5
((1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indol-1-yl)pro-
pan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic
acid 3-(3-fluorophenyl)-3-(3-phenyl-indol-1-yl)-2-hydroxy-propyl
ester and methylamine (2N solution in methanol); MS (ESI) m/z 375
([M+H].sup.+); HRMS: calcd for C24H23FN2O+H+, 375.18672; found
(ESI, [M+H]+), 375.1886.
Example 99
7-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-
-1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00105##
[1105] Step 1: A mixture of sodium perborate tetrahydrate (65 g,
422 mmol) in glacial acetic acid (250 mL) was stirred at 80.degree.
C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50
mL) was added slowly to the mixture. The temperature was maintained
between 80-90.degree. C. for 1 hour. The cooled reaction mixture
was poured into water and extracted twice with diethyl ether. The
combined organic layers were washed with a dilute solution of
sodium bicarbonate, dried over anhydrous magnesium sulfate and
evaporated. The residue was purified via Biotage chromatography
(FlasH90i, silica, 10% THF/hexane) and the product washed with
hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI)
m/z 160 ([M+H].sup.+).
[1106] Step 2: To a solution of 2,6-difluoronitrobenzene (5.0 g,
31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added
potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL,
31.44 mmol). The reaction mixture was heated to 65.degree. C. and
stirred for 24 hours. After cooling to room temperature, the
mixture was neutralized with a dilute aqueous solution of
hydrochloric acid and extracted with diethyl ether. The ethereal
layer was dried over anhydrous magnesium sulfate, and concentrated
in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g
(54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS
(ESI) m/z 272 [M+H].sup.+).
[1107] Step 3: 2-(6-Fluoro-2-nitro-phenyl)-malonic acid dimethyl
ester (12 g, 44 mmol) in a 6N aqueous solution of hydrochloric acid
(200 mL) was heated at reflux for 4 hours. The mixture was cooled,
diluted with 250 mL of water and extracted with diethyl ether. The
ethereal layer was dried over anhydrous magnesium sulfate, and
concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane
gave 7.6 g of (6-fluoro-2-nitro-phenyl)-acetic acid (54%). MS (ESI)
m/z 200 ([M+H].sup.+).
[1108] Step 4: A mixture of (6-fluoro-2-nitro-phenyl)-acetic acid
(9.6 g, 48 mmol) and 10% palladium on carbon (1.3 g) in acetic acid
(100 ml) was hydrogenated at 50 psi for 24 hours. The catalyst was
removed by filtration through Celite and the solvent was
evaporated. The residue was then dissolved in ethanol (100 mL) and
pyridinium para-toluenesulfonate (50 mg) was added and the mixture
heated at reflux for 1 hour s. The mixture was cooled, poured into
water, extracted with ethyl acetate and dried over anhydrous
magnesium sulfate. The solvent was filtered and concentrated in
vacuo. The solid was triturated with 5% ethyl acetate/hexane to
give 6.0 g (83%) 7-fluoro-1,3-dihydro-indol-2-one. MS (ESI) m/z
152, [M+H].sup.+).
[1109] Step 5: 7-Fluoro-1,3-dihydro-indol-2-one (7.3 g, 48 mmol)
and lithium chloride (6.67 g, 158 mmol) were dissolved in
tetrahydrofuran (200 mL). The solution was cooled to -78.degree. C.
and n-butyllithium (40 mL, 100 mmol) was added slowly over a 15
minute period. After 20 minutes at -78.degree. C., methyl iodide (6
mL, 96 mmol) was added and the mixture allowed to warm to room
temperature. After 24 hours, the mixture was poured into water and
extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The crude
product was purified via Biotage chromatography (Flash40i, silica,
10% then 20% ethyl acetate/hexane) gave 4.1 g (48%)
7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one. MS (ESI) m/z 180,
[M+H].sup.+).
[1110] Step 6: A mixture of sodium hydride (244 mg, 6.1 mmol, 60%
in mineral oil) and
7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.1 g, 6.1 mmol)
in dry N,N-dimethylformamide (3.5 mL) was stirred at room
temperature for 20 minutes. [(2R,3R)-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4, 460 mg, 3.0 mmol) was added and the mixture
was heated to 60.degree. C. under nitrogen. After 20 minutes,
additional [(2R,3R)-3-phenyloxiran-2-yl]methanol (230 mg) was added
followed by another addition of
[(2R,3R)-3-phenyloxiran-2-yl]methanol (230 mg) 30 minutes later.
The reaction was monitored by tic (1:1 hexane:ethyl acetate) for
the disappearance of starting epoxide. The reaction mixture was
poured into a 2N aqueous solution of hydrochloric acid and diluted
with ethyl acetate. The layers were separated and the organic layer
was washed with water and brine. The organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to
give 1.8 g of a yellow oil as crude product. The crude product was
purified via Biotage chromatography (FlasH40i, silica, 6:1 to 1:1
hexane:ethyl acetate) to yield 450 mg (23%) of
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-7-fluoro-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one as a yellow oil. MS (ESI) m/z 330
[(M+H).sup.+].
[1111] Step 7: A solution of
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-7-fluoro-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one (870 mg, 2.6 mmol) in dry pyridine (7.5 mL) was
cooled to 0.degree. C. para-Toluenesulfonyl chloride (524 mg, 2.75
mmol) and 4-dimethylaminopyridine (50 mg) were added and the
reaction was allowed to warm to room temperature and stirred
overnight. The reaction was poured into an ice cold 2N aqueous
solution of hydrochloric acid and extracted with ethyl acetate. The
organic layer was washed with water and brine. The organic layer
was dried over anhydrous sodium sulfate, filtered and concentrated
in vacuo to give 1.2 g of a viscous oil. The crude product was
purified via Biotage chromatography (FlasH40i, silica, 16% then 20%
ethyl acetate/hexane) gave 200 mg (22%) of
1-[(1S,2S)-3-chloro-2-hydroxy-1-phenylpropyl]-7-fluoro-3,3-dimethyl-1,3-d-
ihydro-2H-indol-2-one. MS (ESI) m/z 348 [(M+H).sup.+].
[1112] Step 8: A solution of
1-[(1S,2S)-3-chloro-2-hydroxy-1-phenylpropyl]-7-fluoro-3,3-dimethyl-1,3-d-
ihydro-2H-indol-2-one (300 mg, 0.86 mmol), sodium iodide (10 mg),
and methylamine (8M solution in ethanol) was heated to 60.degree.
C. for 1 h. The reaction was cooled to room temperature,
concentrated in vacuo and pre-adsorbed onto Celite. The crude
product was purified via Biotage chromatography (FlasH40i, silica,
5%, 8% and 10% methanol with ammonia/dichloromethane) to give 187
mg of the free base. The free base was dissolved in a minimum
amount of dichloromethane and treated with a 1M ethereal solution
of hydrochloric acid until the pH=3 followed by diethyl ether. The
product was crystallized by adding a minimum of hexane to afford
the title compound
7-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one hydrochloride as a white solid. MS
(ESI) m/z 343 ([M+H].sup.+); HRMS: calcd for
C20H23FN2O.sub.2+H.sup.+, 343.18163; found (ESI, [M+H].sup.+),
343.1804.
Example 100
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dihy-
dro-2H-indol-2-one Hydrochloride
##STR00106##
[1114] Step 1: In an analogous manner to EXAMPLE 99, step 6
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indo-
l-2-one was prepared from
3,3-dimethyl-1,3-dihydro-indol-2-one.sup.10 and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 311 ([M+H].sup.+). .sup.10 A. Kende, Synth. Comm. 1: 12
(1982)
[1115] Step 2: In an analogous manner to EXAMPLE 99, step 7
1-[(1S,2S)-3-chloro-2-hydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-
-indol-2-one was prepared from
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indo-
l-2-one. MS (ESI) m/z 330 ([M+H].sup.+.
[1116] Step 3: In an analogous manner to EXAMPLE 99, step 8
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-1,3-dih-
ydro-2H-indol-2-one hydrochloride was prepared from
1-[(1S,2S)-3-chloro-2-hydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-
-indol-2-one. MS (ESI) m/z 325 ([M+H).sup.+], HRMS: calcd for
C20H24N2O2+H.sup.+, 325.19105; found (ESI-FTMS, [M+H]1.sup.+),
325.19093.
Example 101
7-fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,-
3-dimethyl-1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00107##
[1118] Step 1: A mixture of
7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (EXAMPLE 99, step
5, 1.0 g; 5.58 mmol) and sodium tert-butoxide (1.0 g, 11.16 mmol)
in dry dichloromethane (15 mL) was stirred at room temperature
under nitrogen for 20 minutes. Titanium isopropoxide (2.0 mL, 6.70
mmol) was added to a solution of
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3, 844 mg, 5.02 mmol) in dry dichloromethane (6 mL) and stirred for
20 minutes at room temperature. The epoxide complex was added
drop-wise to the mixture of tert-butoxide and allowed to stir for 4
days. The reaction mixture was poured into a 2N aqueous solution of
hydrochloric acid and diluted with ethyl acetate. The layers were
separated, and the organic layer was washed with water and brine.
The organic layer was dried over anhydrous sodium sulfate, filtered
and concentrated in vacuo to give 2.0 g of crude product. The crude
product was purified via Isco chromatography (RediSep, silica,
gradient of 0% to 100% ethyl acetate in hexane) to yield 600 mg
(31%) of
(2S,3S)-7-Fluoro-1-[1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-3,3-dimethy-
l-1,3-dihydro-indol-2-one as an oil. MS (ESI) m/z 348
([M+H].sup.+).
[1119] Step 2: In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-3-(3-fluoro-phenyl-
)-2-hydroxy-propyl ester was prepared from
(2S,3S)-7-fluoro-1-[1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-3,3-dimethy-
l-1,3-dihydro-indol-2-one. MS (ESI) m/z 502 ([M+H].sup.+).
[1120] Step 3: In an analogous manner to EXAMPLE 5
7-fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3-
,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride was prepared
from (2S,3S)-toluene-4-sulfonic acid
3-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-3-(3-fluoro-phenyl-
)-2-hydroxy-propyl ester. MS (ESI) m/z 360 ([M+H].sup.+), HRMS:
calcd for C20H22F2N2O2+H.sup.+, 361.17221; found (ESI,
[M+H].sup.+), 361.1719.
Example 102
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol
Hydrochloride
##STR00108##
[1122] Step 1: Thiophene (2.42 mL, 30.6 mmol) was dissolved in
tetrahydrofuran (50 mL), cooled to -78.degree. C., and treated with
n-butyllithium (9.2 mL, 18.4 mmol) then warmed to 25.degree. C. The
mixture was stirred for 30 minutes then cooled to -78.degree. C.
and a solution of 2,3-O-isopropylidene-D-glyceraldehyde.sup.11
(2.00 g, 15.3 mmol) in tetrahydrofuran (15.3 mL) was added
dropwise. Stirring was continued for 20 minutes then warmed to
0.degree. C. and quenched with a saturated aqueous solution of
ammonium chloride. The mixture was diluted with ethyl acetate,
washed with water, and saturated brine. The organic layer was
separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The crude product was purified via Biotage
chromatography (FlasH40i, silica, 10% acetone/hexane) to afford the
product 1.6 g (51%) as a 2:1 mixture of
(R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol and
(S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol as an
oil. HRMS: calcd for C.sub.16H.sub.18N.sub.2OS+H+, 287.12126; found
(ESI, [M+H]+), 287.1204. .sup.11 Schmid, C. R.; Bryant, J. D.;
Dowlatzedah, M.; Phillips, J. L.; Prather, D. E.; Schantz, R. D.;
Sear, N. L.; Vianco, C. S. J. Org. Chem. 1991, 56, 4056.
[1123] Step 2: A mixture of
(R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol and
(S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol (1.5
g, 7.0 mmol) was dissolved in tetrahydrofuran (28 mL) and sodium
acetylide (2.1 g, 7.7 mmol; 18 wt % slurry in xylenes/light mineral
oil) and the mixture was stirred for 2 hours. para-Toluenesulfonyl
chloride (1.46 g, 7.7 mmol) was added and stirring was continued
for 2 hours, then indoline (2.5 g, 21 mmol) was added followed by
2,6-lutidine (0.81 mL, 7.0 mmol). After 72 hours the mixture was
quenched with a saturated aqueous solution of ammonium chloride,
diluted with ethyl acetate, washed with water, and saturated brine.
The organic layer was separated, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product was
purified via Isco chromatography (Redisep, silica, gradient 1-10%
ethyl acetate in hexane) to afford 590 mg that was immediately
dissolved in dioxane (10 mL) and treated with
dichlorodicyanobenzoquinone (552 mg, 2.4 mmol) and stirred for 30
minutes. The mixture was diluted with ethyl acetate and washed with
saturated sodium bicarbonate, water, and saturated brine. The
organic layer was separated, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product was
purified via Isco chromatography (Redisep, silica, gradient 1-20%
ethyl acetate in hexane) to afford 355 mg of
1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole.
HRMS: calcd for C.sub.18H.sub.19NO.sub.2S+H+, 314.12092; found
(ESI-FTMS, [M+H]1+), 314.12111.
[1124] Step 3:
1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole
(350 mg, 1.12 mmol) was dissolved in methanol (20 mL) and
benzenesulfonic acid (17 mg, 0.11 mmol) was added. The mixture was
stirred for 6 hours then diluted with ethyl acetate and washed with
a saturated aqueous solution of sodium bicarbonate, water, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via flash column chromatography
(silica, 5% methanol/chloroform) to afford 260 mg (82%) of
(2S,3S)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol. HRMS: calcd
for C.sub.15H.sub.15NO.sub.2S+H+, 274.08963; found (ESI, [M+H]+),
274.0892.
[1125] Step 4:
(2S,3S)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol (250 mg,
0.91 mmol) was dissolved in pyridine (3 mL), para-toluenesulfonyl
chloride (216 mg, 1.13 mmol) was added and the mixture was stirred
for 2 hours. The mixture was diluted with ethyl acetate and washed
with water, a saturated aqueous solution of copper sulfate, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, gradient 0%-100% ethyl acetate in hexane) to afford 360 mg
that was immediately dissolved in methylamine (8M solution in
ethanol, 15 mL) and stirred for 16 hours. The mixture was
concentrated in vacuo and purified via flash column chromatography
(silica, gradient 2%-10% methanol saturated with ammonia in
chloroform) to give 180 mg of
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol
as a colorless oil. The freebase was dissolved in ether (5 mL) and
treated with a 1N ethereal solution of hydrochloric acid (0.63 mL,
0.63 mmol, 1 equivalent). The white precipitate was collected and
dried under vacuum to give 193 mg (60%) of
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol
hydrochloride. HRMS: calcd for C.sub.16H.sub.18N.sub.2OS+H+,
287.12126; found (ESI, [M+H]+), 287.1204
Example 103
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol
Hydrochloride
##STR00109##
[1127] Step 1: Thiophene (2.42 mL, 30.6 mmol) was dissolved in
tetrahydrofuran (50 mL), cooled to -78.degree. C., and treated with
n-butyllithium (9.2 mL, 18.4 mmol) then warmed to 25.degree. C. The
mixture was stirred for 30 minutes then cooled to -78.degree. C.
and a solution of 2,3-O-isopropylidene-D-glyceraldehyde.sup.11
(2.00 g, 15.3 mmol) in tetrahydrofuran (15.3 mL) was added
dropwise. Stirring was continued for 20 minutes then warmed to
0.degree. C. and quenched with a saturated aqueous solution of
ammonium chloride. The mixture was diluted with ethyl acetate,
washed with water, and saturated brine. The organic layer was
separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The crude product was purified via Biotage
chromatography (FlasH40i, silica, 10% acetone/hexane) to afford the
product 1.6 g (51%) as a 2:1 mixture of
(R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol and
(S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol as an
oil. HRMS: calcd for C.sub.16H18N.sub.2OS+H+, 287.12126; found
(ESI, [M+H]+), 287.1204.
[1128] Step 2: A mixture of
(R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol and
(S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol (1.5
g, 7.0 mmol) was dissolved in tetrahydrofuran (28 mL) and sodium
acetylide (2.1 g, 7.7 mmol; 18 wt % slurry in xylenes/light mineral
oil) and the mixture was stirred for 2 hours. para-Toluenesulfonyl
chloride (1.46 g, 7.7 mmol) was added, and stirring was continued
for 2 hours, then indoline (2.5 g, 21 mmol) was added followed by
2,6-lutidine (0.81 mL, 7.0 mmol). After 72 hours the mixture was
quenched with a saturated aqueous solution of ammonium chloride,
diluted with ethyl acetate, washed with water, and saturated brine.
The organic layer was separated, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product was
purified via Isco chromatography (Redisep, silica, gradient 1-10%
ethyl acetate in hexane) to afford 590 mg that was immediately
dissolved in dioxane (10 mL) and treated with
dichlorodicyanobenzoquinone (552 mg, 2.4 mmol) and stirred for 30
minutes. The mixture was diluted with ethyl acetate and washed with
a saturated aqueous solution of sodium bicarbonate, water, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, gradient 1-20% ethyl acetate in hexane) to afford 160 mg of
1-[(R)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole.
HRMS: calcd for C.sub.18H.sub.19NO.sub.2S+H+, 314.12092; found
(ESI-FTMS, [M+H]1+), 314.12089.
[1129] Step 3:
1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole
(160 mg, 0.51 mmol) was dissolved in methanol (10 mL) and
benzenesulfonic acid (10 mg, 0.06 mmol) was added. The mixture was
stirred for 16 hours then diluted with ethyl acetate and washed
with a saturated aqueous solution of sodium bicarbonate, water, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via flash column chromatography
(silica, 5% methanol/chloroform) to afford 102 mg (74%) of
(2S,3R)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol that was
carried directly to the next step.
[1130] Step 4:
(2S,3R)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol (102 mg,
0.37 mmol) was dissolved in pyridine (1.5 mL), para-toluenesulfonyl
chloride (88 mg, 0.46 mmol) was added and the mixture was stirred
for 16 hours. The mixture was diluted with ethyl acetate and washed
with water, a saturated aqueous solution of copper sulfate, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, gradient 0%-100% ethyl acetate in hexane) to afford 140 mg
that was immediately dissolved in methylamine (8M solution in
ethanol, 15 mL) and stirred for 3 hours. The mixture was
concentrated in vacuo and purified via flash column chromatography
(silica, gradient 2%-10% methanol saturated with ammonia in
chloroform) to give 65 mg (71%) of
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol
as a colorless oil. The freebase was dissolved in diethyl ether (5
mL) and treated with a 1N ethereal solution of hydrochloric acid
(0.23 mL, 0.23 mmol, 1 equivalent). The white precipitate was
collected and dried under vacuum to give
(1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol
hydrochloride. HRMS: calcd for C.sub.16H.sub.18N.sub.2OS+H+,
287.12126; found (ESI, [M+H]+), 287.1209
Example 104
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1,-
3'-indol]-2'(1'H)-one Hydrochloride
##STR00110##
[1132] Step 1: Spiro[cyclohexane-1,3'-indol]-2'(1'H)-one.sup.12
(0.82 g, 4.1 mmol) was dissolved in N,N-dimethylformamide (1 mL),
and sodium hydride (168 mg, 4.4 mmol, 60% wt suspension in mineral
oil) was added and the resulting mixture was stirred for 15
minutes. The mixture was warmed to 75.degree. C. and
trans-3-phenylglycidol (306 mg, 2.04 mmol) was added in four
portions. Stirring was continued for 2 hours, then the reaction
mixture was cooled and quenched with a saturated aqueous solution
of ammonium chloride. The mixture was diluted with ethyl acetate,
washed with water, and saturated brine. The organic layer was
separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The crude product was purified via Isco
chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate
in hexane) to afford 290 mg (41%) of
1'-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]spiro[cyclohexane-1,3'-indol]-2-
'(1'H)-one as an oil. HPLC purity 100% at 210-370 nm, 9.4 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes,
hold 4 min. .sup.12Fensome, A.; Miller, L. L.; Ulirich, J. W.;
Bender, R. H. W.; Zhang, P.; Wrobel, J. E.; Zhi, L.; Jones, T. K.;
Marschke, K. B.; Tegley, C. M. PCT Int. PCT Int. Appl. 2000, 127
pp. WO2000066556
[1133] Step 2:
1'-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]spiro[cyclohexane-1,3'-indol]-2-
'(1'H)-one (250 mg, 0.71 mmol) was dissolved in pyridine (2.5 mL)
and para-toluenesulfonyl chloride (169 mg, 0.89 mmol) was added.
The reaction was stirred for 5 hours, then the reaction mixture was
diluted with ethyl acetate and washed with water, a saturated
aqueous solution of copper sulfate, a 2N aqueous solution of
hydrochloric acid, and saturated brine. The organic layer was
separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The crude product was immediately dissolved
in methylamine (8M solution in ethanol, 15 mL) and stirred for 16
hours. The mixture was concentrated in vacuo and purified via flash
column chromatography (silica, 5% methanol saturated with ammonia
in chloroform) to give 85 mg (32%)
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1-
,3'-indol]-2'(1'H)-one as a colorless oil. The freebase was
dissolved in diethyl ether (5 mL) and treated with a 1N ethereal
solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent).
The white precipitate was collected and dried under vacuum to give
193 mg (60%) of
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1-
,3'-indol]-2'(1'H)-one hydrochloride. HRMS: calcd for
C.sub.23H.sub.28N.sub.2O.sub.2+H+, 365.22235; found ([M+H]+),
365.2226;
Example 105
(1S,2R)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethan-
ol Hydrochloride
##STR00111##
[1135] Step 1: To a suspension of
3-fluorobenzyltriphenylphosphonium bromide (6.8 g, 15 mmol) in
tetrahydrofuran (50 mL) at 0.degree. C. was added sodium hydride
(0.57 g, 15 mmol, 60% wt suspension in mineral oil), and the
mixture was stirred for 1 hour s. A solution of
(S)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester.sup.13
(2.5 g, 12.5 mmol) in tetrahydrofuran (10 mL) was added and the
mixture was stirred for 1 hour then warmed to 25.degree. C. and
quenched with a saturated aqueous solution of ammonium chloride.
The mixture was diluted with ethyl acetate, washed with water, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, 10% ethyl acetate/hexane) to afford 2.18 g (60%) of
tert-butyl
(2S)-2-[(E)-2-(3-fluorophenyl)vinyl]pyrrolidine-1-carboxylate as a
colorless oil that crystallized on standing. HRMS: calcd for
C.sub.17H.sub.22FNO.sub.2+H+, 292.17073; found (ESI, M+H),
292.1713. .sup.13 Cook, G. R.; Stille, J. R. Tetrahedron, 1994,
50(14), 4105.
[1136] Step 2: tert-Butyl
(2S)-2-[(E)-2-(3-fluorophenyl)vinyl]pyrrolidine-1-carboxylate (400
mg, 1.37 mmol) was dissolved in dichloromethane (50 mL). A
saturated aqueous solution of sodium bicarbonate (50 mL) was added,
followed by acetone (10 mL) and tetrabutylammonium hydrogen sulfate
(46 mg, 0.14 mmol).
[1137] With vigorous stirring Oxone (8.4 g, 13.7 mmol) was added
over 2 hours in 8 portions (1.05 g every 15 minutes). The mixture
was stirred an additional 16 hours then diluted with
dichloromethane. The organic layer was separated and washed with
water, and saturated brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
via Isco chromatography (Redisep, silica, 20% ethyl acetate/hexane)
to give 240 mg that was immediately combined with indoline (0.14 g,
1.2 mmol) and heated to 90.degree. C. for 16 hours. The mixture was
cooled and the crude orange oil was purified by Isco chromatography
(Redisep, silica, gradient 0% to 25% ethyl acetate in hexane) to
give 130 mg that was immediately dissolved in dichloromethane (20
mL). Manganese dioxide (0.86 g, 10 mmol) was added and the mixture
was stirred for 5 hours, then diluted with dichloromethane and
filtered through a pad of Celite and concentrated. The crude
product was purified by Isco chromatography (Redisep, silica,
gradient 0% to 50% ethyl acetate in hexane) to give 50 mg of
(S)-2-[2-(R)-(3-fluoro-phenyl)-1-hydroxy-2-indol-1-yl-ethyl]-(S)-pyrrolid-
ine-1-carboxylic acid tert-butyl ester.
[1138] Step
3:(S)-2-[2-(R)-(3-Fluoro-phenyl)-1-hydroxy-2-indol-1-yl-ethyl]-(S)-pyrrol-
idine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) was
dissolved in methanol (1 mL) and a 1N ethereal solution of
hydrochloric acid (0.96 mL, 0.96 mmol) was added. After 6 hours the
mixture was concentrated and purified via flash column
chromatography (silica, 10% methanol saturated with ammonia in
chloroform) to give 6 mg (15%)
(1S,2R)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]etha-
nol. The freebase was dissolved in diethyl ether (2 mL) and treated
with a 1N ethereal solution of hydrochloric acid (0.02 mL, 0.02
mmol, 1 equivalent). The white precipitate was collected and dried
under vacuum to give 4 mg of
(1S,2R)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]etha-
nol hydrochloride. HRMS: calcd for C.sub.20H.sub.21FN.sub.2O+H+,
325.17107; found (ESI, [M+H]+), 325.1712
Example 106
(1R,2S)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethan-
ol Hydrochloride
##STR00112##
[1140] Step 1: To a suspension of
3-fluorobenzyltriphenylphosphonium bromide (6.8 g, 15 mmol) in
tetrahydrofuran (50 mL) at 0.degree. C. was added sodium hydride
(0.57 g, 15 mmol, 60% wt suspension in mineral oil) and the mixture
was stirred for 1 hour at room temperature. A solution of
(S)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester.sup.13
(2.5 g, 12.5 mmol) in tetrahydrofuran (10 mL) was added, and the
mixture was stirred for 1 hour then warmed to 25.degree. C. and
quenched with a saturated aqueous solution of ammonium chloride.
The mixture was diluted with ethyl acetate, washed with water, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, 10% ethyl acetate/hexane) to afford 2.18 g (60%) of
tert-butyl
(2S)-2-[(E)-2-(3-fluorophenyl)vinyl]pyrrolidine-1-carboxylate as a
colorless oil that crystallized on standing. HRMS: calcd for
C.sub.17H.sub.22FNO.sub.2+H+, 292.17073; found (ESI, M+H),
292.1713.
[1141] Step 2: tert-Butyl
(2S)-2-[(E)-2-(3-fluorophenyl)vinyl]pyrrolidine-1-carboxylate (400
mg, 1.37 mmol) was dissolved in dichloromethane (50 mL). A
saturated aqueous solution of sodium bicarbonate (50 mL) was added,
followed by acetone (10 mL) and tetrabutylammonium hydrogen sulfate
(46 mg, 0.14 mmol). With vigorous stirring Oxone (8.4 g, 13.7 mmol)
was added over 2 hours in 8 portions (1.05 g every 15 minutes). The
mixture was stirred an additional 16 hours then diluted with
dichloromethane. The organic layer was separated and washed with
water, and saturated brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
via Isco chromatography (Redisep, silica, 20% ethyl acetate/hexane)
to give 240 mg that was immediately combined with indoline (0.14 g,
1.2 mmol) and heated to 90.degree. C. for 16 hours. The mixture was
cooled and the crude orange oil was purified by Isco chromatography
(Redisep, silica, gradient 0% to 25% ethyl acetate in hexane) to
give 130 mg that was immediately dissolved in dichloromethane (20
mL). Manganese dioxide (0.86 g, 10 mmol) was added and the mixture
was stirred for 5 hours then diluted with dichloromethane and
filtered through a pad of Celite and concentrated. The crude
product was purified by Isco chromatography (Redisep, silica,
gradient 0% to 50% ethyl acetate in hexane) to give 50 mg of
(R)-2-[2-(S)-(3-fluoro-phenyl)-1-hydroxy-2-indol-1-yl-ethyl]-(S)-pyrrolid-
ine-1-carboxylic acid tert-butyl ester.
[1142] Step
3:(R)-2-[2-(S)-(3-Fluoro-phenyl)-1-hydroxy-2-indol-1-yl-ethyl]-(S)-pyrrol-
idine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) was
dissolved in methanol (1 mL) and a 1N ethereal solution
hydrochloric acid (1.0 mL, 1.0 mmol) was added. After 16 hours the
mixture was concentrated and purified via flash column
chromatography (silica, 10% methanol saturated with ammonia in
chloroform) to give 19 mg (50%)
(1R,2S)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]etha-
nol. The freebase was dissolved in diethyl ether (2 mL) and treated
with 1N ethereal solution of hydrochloric acid (0.06 mL, 0.06 mmol,
1 equivalent). The white precipitate was collected and dried under
vacuum to give 17 mg of
(1R,2S)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]etha-
nol hydrochloride. HRMS: calcd for C.sub.20H.sub.21FN.sub.2O+H+,
325.17107; found (ESI, [M+H]+), 325.1711
Example 107
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-butane-1,-
3'-indol]-2'(1'H)-one Hydrochloride
##STR00113##
[1144] Step 1: In an analogous manner to EXAMPLE 104, step 1
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro[cyclobutane-1,3'-indol]-2'-
(1'H)-one was prepared from
spiro[cyclobutane-1,3'-indol]-2'(1'H)-one.sup.12 and
trans-3-phenylglycidol. HPLC purity 100% at 210-370 nm, 8.4 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes,
hold 4 min.
[1145] Step 2: In an analogous manner to EXAMPLE 104, step 2
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-butane-1-
,3'-indol]-2'(1'H)-one hydrochloride was prepared from
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro-[cyclobutane-1,3'-indol]-2-
'(1'H)-one. HRMS: calcd for C.sub.21H.sub.24N.sub.2O.sub.2+H+,
337.19105; found (ESI, [M+H]+), 337.1917
Example 108
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro-[cyclopentane-1-
,3'-indol]-2'(1'H)-one Hydrochloride
##STR00114##
[1147] Step 1: In an analogous manner to EXAMPLE 104, step 1
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro[cyclopentane-1,3'-indol]-2-
'(1'H)-one was prepared from
spiro[cyclopentane-1,3'-indol]-2'(1'H)-one.sup.12 and
trans-3-phenylglycidol. HRMS: calcd for
C.sub.21H.sub.23NO.sub.3+H+, 338.17507; found (ESI, [M+H]+),
338.1769
[1148] Step 2: In an analogous manner to EXAMPLE 104, step 2
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro-[cyclopentane--
1,3'-indol]-2'(1'H)-one hydrochloride was prepared from
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro-[cyclopentane-1,3'-indol]--
2'(1'H)-one. HRMS: calcd for C.sub.22H.sub.26N.sub.2O.sub.2+H+,
351.20670; found (ESI, [M+H]+), 351.2061
Example 109
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro-[cyclopropane-1-
,3'-indol]-2'(1'H)-one Hydrochloride
##STR00115##
[1150] Step 1: In an analogous manner to EXAMPLE 104, step 1
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro[cyclopropane-1,3'-indol]-2-
'(1'H)-one was pre-pared from
spiro[cyclopropane-1,3'-indol]-2'(1'H)-one.sup.14 and
trans-3-phenylglycidol. HPLC purity 89.1% at 210-370 nm, 7.7 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes,
hold 4 min. .sup.14 Roberston, D. W.; Krushinski, J. H.; Pollock,
G. D.; Wilson, H.; Kauffman, R. F.; Hayes, J. S. J. Med. Chem.
1987, 30, 824.
[1151] Step 2: In an analogous manner to EXAMPLE 104, step 2
1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro-[cyclopropane--
1,3'-indol]-2'(1'H)-one hydrochloride was prepared from
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-spiro[cyclopropane-1,3'-indol]--
2'(1'H)-one. HRMS: calcd for C.sub.20H.sub.22N.sub.2O.sub.2+H+,
323.17540; found (ESI, [M+H]+), 323.1744
Example 110
5-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-
-1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00116##
[1153] Step 1: 5-Fluoro-1,3-dihydro-indol-2-one (2.0 g, 13.2 mmol)
and lithium chloride (1.39 g, 33.0 mmol) were dissolved in
tetrahydrofuran (40 mL) and cooled to 0.degree. C. n-Butyllithium
(10.6 mL, 26.4 mmol) was added dropwise and the mixture was stirred
20 minutes. Methyl iodide (1.63 mL, 26.4 mmol) was added slowly and
stirring was continued for 2 hours at 0.degree. C. then warmed to
25.degree. C. After 16 hours the reaction was quenched with a
saturated aqueous solution of ammonium chloride. The mixture was
diluted with ether, washed with water, and saturated brine. The
organic layer was separated, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product was
purified via Isco chromatography (Redisep, silica, gradient 10% to
50% ethyl acetate in hexane) to afford 1.18 g (50%) of
5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as white crystals.
HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u,
150.times.4.6 mm column, 1.2 mL/minutes, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 minutes, hold 4 min.
[1154] Step 2: In an analogous manner to EXAMPLE 104, step
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-5-fluoro-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one was prepared from
5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and
trans-3-phenylglycidol. HRMS: calcd for
C.sub.19H.sub.20FNO.sub.3+H+, 330.15000; found (ESI, [M+H]+),
330.1495
[1155] Step 3: In an analogous manner to EXAMPLE 104, step 2
5-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one hydrochloride was prepared from
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-5-fluoro-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one. HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra
RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes, hold 4
minutes. HRMS: calcd for C.sub.20H.sub.23FN.sub.2O.sub.2+H+,
343.18163; found (ESI, [M+H]+), 343.184
Example 111
(1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2--
ol Hydrochloride
##STR00117##
[1157] Step 1:
(2S,3S)-3-(3-Fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol
(example 47, step 5) (0.6 g, 2.1 mmol) was dissolved in pyridine (5
mL) and para-toluenesulfonyl chloride (0.44 g, 2.3 mmol) was added.
The mixture was stirred for 3 hours then the reaction mixture was
diluted with ethyl acetate and washed with water, followed by a
saturated aqueous solution of copper sulfate, a 2N aqueous solution
of hydrochloric acid, and saturated brine. The organic layer was
separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. The crude product was immediately dissolved
in methylamine (8M solution in ethanol, 25 mL) and stirred for 16
hours. The mixture was concentrated in vacuo and purified via flash
column chromatography (silica, 5% methanol saturated with ammonia
in chloroform) to give
(1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-
-ol as a colorless oil. The freebase was dissolved in diethyl ether
(5 mL) and treated with a 1N ethereal solution of hydrochloric acid
(1 equivalent). The white precipitate was collected and dried under
vacuum to give 80 mg (12%) of
(1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-
-ol hydrochloride. HRMS: calcd for C.sub.20H.sub.21FN.sub.2O+H+,
325.17107; found (ESI, [M+H]+), 325.1728.
Example 112
7'-fluoro-1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-spiro[cycl-
ohexane-1,3'-indol]-2'(1'H)-one Hydrochloride
##STR00118##
[1159] Step 1: 7-Fluoro-1,3-dihydro-indol-2-one (EXAMPLE 99, step
4) (1.16 g, 7.68 mmol) and lithium chloride (0.81 g, 19.2 mmol)
were dissolved in tetrahydrofuran (50 mL) and cooled to 0.degree.
C. n-Butyllithium (6.14 mL, 15.4 mmol) was added dropwise and the
mixture was stirred 15 minutes. 1,5-Dibromopentane (1.05 mL, 7.7
mmol) was added slowly and stirring was continued for 2 hours at
0.degree. C. then warmed to 25.degree. C. After 16 hours the
reaction was quenched with a saturated aqueous solution of ammonium
chloride. The mixture was diluted with ether, washed with water,
and saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, gradient 5% to 40% ethyl acetate in hexane) to afford 0.90
g (54%) of 7'-fluorospiro-[cyclohexane-1,3'-indol]-2'(1'H)-one.
HPLC purity 95.9% at 210-370 nm, 19.2 min.; Xterra MSC18, 5u,
150.times.3.0 mm column, 0.5 mL/minutes, 95/5-5/95 (0.1% formic
acid in H2O/MeOH) for 20 minutes, hold 3 min.
[1160] Step 2: In an analogous manner to EXAMPLE 104, step 1
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-7'-fluorospiro[cyclohexane-1,3'-
-indol]-2'(1'H)-one was pre-pared from
7'-fluorospiro-[cyclohexane-1,3'-indol]-2'(1'H)-one and
trans-3-phenylglycidol. HRMS: calcd for C22H24FNO3+H+, 370.18130;
found (ESI, [M+H]+), 370.1798
[1161] Step 3: In an analogous manner to EXAMPLE 104, step 2
7'-fluoro-1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-spiro[cyc-
lohexane-1,3'-indol]-2'(1'H)-one hydrochloride was prepared from
1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-7'-fluorospiro[cyclohexane-1,3'-
-indol]-2'(1'H)-one. HRMS: calcd for
C.sub.23H.sub.27FN.sub.2O.sub.2+H+, 383.21293; found (ESI, [M+H]+),
383.2109
Example 113
5'-bromo-1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-spiro[cyclo-
hexane-1,3'-indol]-2'(1'H)-one Hydrochloride
##STR00119##
[1163] Step 1: In an analogous manner to EXAMPLE 104, step 1
5'-bromo-1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro[cyclohexane-1,3'--
indol]-2'(1'H)-one was prepared from
5'-bromospiro[cyclohexane-1,3'-indol]-2'(1'H)-one.sup.12 and
trans-3-phenylglycidol. HRMS: calcd for C22H24BrNO3+H+, 430.10123;
found (ESI, [M+H]+), 430.1006
[1164] Step 2: In an analogous manner to EXAMPLE 104, step 2
5'-bromo-1'-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-spiro[cycl-
ohexane-1,3'-indol]-2'(1'H)-one hydrochloride was prepared from
5'-bromo-1'-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]spiro[cyclohexane-1,3'--
indol]-2'(1'H)-one. HRMS: calcd for C23H27BrN2O2+H+, 443.13286;
found (ESI, [M+H]+), 443.1333.
Example 114
(1S,2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indol-1-yl]-3-(methyla-
mino)propan-2-ol Hydrochloride
##STR00120##
[1166] Step 1: To a solution of
(2S,3S)-3-indol-1-yl-3-(3-fluorophenyl)-propane-1,2-diol (EXAMPLE
47, Step 5, 1.34 g, 4.56 mmol) in N,N-dimethylformamide (20 mL) was
added pulverized solid potassium hydroxide (0.76 g, 13.68 mmol).
The mixture was stirred for 15 minutes under nitrogen at room
temperature, whereupon iodine (1.21 g, 4.72 mmol) was added in one
portion. The mixture was stirred for 30 minutes at room
temperature, then poured into 100 mL of a 5% aqueous sodium
thiosulfate solution. The solution was extracted 3 times with ethyl
acetate and the combined extracts were washed 3 times with water.
The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
via Biotage chromatography (FlasH40i, silica, 40% ethyl
acetate/hexane) to yield 0.91 g (48%) of
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
as a dark brown oil. MS (ES) m/z 411.9.
[1167] Step 2: A mixture of
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(0.25 g, 0.61 mmol), 2-fluorobenzeneboronic acid (0.12 g, 0.85
mmol), and potassium phosphate (0.39 g, 1.83 mmol) in
N,N-dimethylformamide (10 mL) was degassed with nitrogen for 5
minutes then a catalytic amount (0.02 g) of
[1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was
added. The solution was heated to 90.degree. C. for 3 hours then
cooled and poured into 100 mL of water. The aqueous mixture was
extracted 3 times with ethyl acetate and the combined extracts were
then washed 2 times with water. The ethyl acetate was dried by
filtration through a plug of silica gel then concentrated. The
residue was purified by Biotage chromatography (FlasH40i, silica,
40% ethyl acetate/hexane) to yield 0.14 g of
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-fluorophenyl]-1H-indol-1-yl}propa-
ne-1,2-diol as an oil, which was used in the next step without
further purification.
[1168] Step 3: In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(2-fluorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-fluorophenyl]-1H-indol-1-yl}propane-1,-
2-diol.
[1169] Step 4: In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluoro-phenyl)-3-[3-(2-fluorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ES) m/z
393.1.
Example 115
(1S,2R)-1-[3-(3,4-dichlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(met-
hylamino)propan-2-ol Hydrochloride
##STR00121##
[1171] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3,4-dichlorophenyl)-3-{3-[2-fluorophenyl]-1H-indol-1-yl}propan-
e-1,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 3,4-dichlorobenzene boronic acid.
[1172] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-[3-(3,4-dichloro-phenyl)-indol-1-yl]-3-(3-fluorophenyl)-2-hydroxy-propy-
l ester was prepared from
(2S,3S)-3-[3-(3,4-Dichloro-phenyl)-indol-1-yl]-3-(3-fluoro-phenyl)-propan-
e-1,2-diol.
[1173] In an analogous mannerto EXAMPLE 5,
(1S,2R)-1-[3-(3,4-dichlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-[3-(3,4-dichloro-phenyl)-indol-1-yl]-3-(3-fluoro-phenyl)-2-hydroxy-prop-
yl ester and methylamine (2N solution in methanol). MS (ES) m/z
443.0.
Example 116
(1S,2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indol-1-yl]-3-(methyla-
mino)propan-2-ol Hydrochloride
##STR00122##
[1175] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-fluorophenyl]-1H-indol-1-yl}propane-1,-
2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 3-florobenzene boronic acid.
[1176] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(3-fluorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-fluorophenyl]-1H-indol-1-yl}propane-1,-
2-diol.
[1177] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluoro-phenyl)-3-[3-(3-fluorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
393.
Example 117
(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol Hydrochloride
##STR00123##
[1179] Step 1: To a mixture of 4-fluoro-phenylamine (9 g, 81 mmol),
concentrated hydrochloric acid (20.4 mL), and water (35.1 mL) was
added sodium nitrite (6.3 g, 89.1 mmol) dissolved in water (7.8
mL). In a separate flask ethyl 2-ethylacetoacetate (14.4 g, 89.1
mmol) in ethanol (63.6 mL) at 0.degree. C. was treated with
potassium hydroxide (5.1 g, 89.1 mmol) in water (7.5 mL) and ice
and the above solution added. The pH of the reaction was adjusted
to 5-6 and the reaction stirred at 0.degree. C. for 3 hours and
then stored in the freezer overnight. The reaction was then
extracted with ethyl acetate (100 mL) and the organics washed with
saturated brine solution (100 mL), dried with anhydrous magnesium
sulfate. Most of the solvent was removed in vacuo before it was
added dropwise to a 14.5% ethanolic solution of hydrochloric acid
(70 mL) at 78.degree. C. Heating was continued for 2 hours. The
solvent was removed in vacuo and the residue treated with
dichloromethane (300 mL) and water (100 mL). The organic layer was
washed with saturated sodium chloride (200 mL), dried over sodium
sulfate and concentrated in vacuo. Purification on a short wash
column (silica gel, 25% ethyl acetate/hexane) gave ethyl
5-fluoro-3-methyl-1H-indole-2-carboxylate as a white solid. MS (ES)
m/z 220.0
[1180] Step 2: Ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate (8.3
g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a
mixture of ethanol (20 mL) and water (15 mL) was heated at reflux
for 1 hour. The volume was reduced to 10 mL under reduced pressure
and the solution brought to an acidic pH with a 3N aqueous solution
of hydrochloric acid. The resulting precipitate was filtered,
washed with water (100 mL) and dried in vacuo at 80.degree. C.
overnight to afford 5-fluoro-3-methyl-1H-indole-2-carboxylic acid
as a white solid. MS (ES) m/z 192.0
[1181] Step 3: 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (8.49
g, 43.9 mmol) and copper metal (0.35 g, 5.5 mmol) in distilled
quinoline (22 mL) was heated to reflux for 3 hours. The copper
powder was filtered off and the filtrate was brought to pH 3 at
0.degree. C. with a 6N aqueous solution of hydrochloric acid. The
solution was extracted with ether (200 mL) and the organics washed
with saturated sodium chloride (200 mL), dried over magnesium
sulfate and concentrated in vacuo to give
5-fluoro-3-methyl-1H-indole as a brown solid. MS (ES) m/z
150.0.
[1182] Step 4: To a solution of diisopropyl D-tartrate (6 mL, 28
mmol) in methylene chloride (800 mL) at -10.degree. C. under
nitrogen was added 4 A molecular sieves (15g), titanium
isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200
mmol). The mixture was allowed to age for 40 minutes at -10.degree.
C., after which time it was cooled to -20.degree. C., and treated
in a dropwise fashion with a solution of tert-butyl hydroperoxide
(TBHP, .about.450 mmol) in isooctane. After 18 hours at -30 to
-15.degree. C., the reaction mixture was treated with a 30% aqueous
solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The
cold bath was removed and the mixture was allowed to warm to
.about.10.degree. C. Magnesium sulfate (anhydrous, 15 g) was added
and the mixture was stirred for 20 minutes. After the solids
settled, the solution was filtered through a pad of silica gel, and
washed with ether (50 mL). The filtrate was concentrated in vacuo
and toluene was added to azeotropically remove the unreacted TBHP.
The residue was then purified using a silica gel column
(hexane:ethyl acetate/3:1) and the purified product was
crystallized from hexane/ethyl acetate to yield
[(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18g, 60%,
98.2% ee). MS (ESI) m/z 151.
[1183] Step 5: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g,
19.5 mmol) and potassium hydride 50% dispersion in mineral oil (2.8
g, 35.1 mmol) in dichloromethane (40 mL) was stirred for 10 minutes
under nitrogen at room temperature. A solution of
[(2R,3R)-3-phenyloxiran-2-yl]methanol (2.0 g, 13.0 mmol) and
titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10
mL) was then added and the mixture was stirred at room temperature
for 12 hours. After disappearance of the epoxide, the mixture was
partitioned between a 1N aqueous solution of hydrochloric acid (50
mL) and ethyl acetate (50 mL). The organic layer was separated,
washed with saturated sodium bicarbonate (50 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
crude product was purified via Biotage chromatography (FlasH40i,
silica, 60% ethyl acetate/hexane) to give
(2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol.
MS (ESI) m/z 300
[1184] Step 6: A solution of
(2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
(1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1
mmol) in anhydrous pyridine (11 ml) was stirred at room temperature
under nitrogen for 12 hours. The reaction was poured into a 1N
aqueous solution of hydrochloric acid (50 mL) and extracted with
ethyl acetate (50 mL). The organics were dried over anhydrous
sodium sulfate, filtered, and concentrated to give
(2S,3S)-toluene-4-sulfonic acid
3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester.
The product was used in the next step without further purification.
To a solution of toluene-4-sulfonic acid
3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester
(1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of
methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred
for 12 hours. Upon completion, the reaction was partitioned between
saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The
organic layer was separated, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
via Biotage chromatography (FlasH40i, silica, 20%
MeOH/dichloromethane) to give
(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol as a clear oil. The free base was dissolved in a minimum
amount of ethanol and treated with a 2N ethereal solution of
hydrochloric acid and stirred for 1 hour. The ethanol was removed
in vacuo and the clear oil was triturated with
ether/dichloromethane to give
(1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol hydrochloride as a white solid. MS (ESI) m/z 313
Example 118
(1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00124##
[1186] To a solution of (2S,3S)-toluene-4-sulfonic acid
3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester
(Intermediate in EXAMPLE 117, step 6, 0.15 g, 0.33 mmol) in
methanol (10 mL) was added concentrated ammonium hydroxide (20 mL),
and the reaction was stirred for 12 hours. Upon completion, the
reaction was partitioned between water (25 mL) and ethyl acetate
(25 mL). The organic layer was separated, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified via Biotage chromatography (FlasH40i, silica,
25% MeOH/dichloromethane) to give
(1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
as a clear oil. The free base was dissolved in a minimum amount of
ethanol and treated with a 4N solution of hydrochloric acid in
dioxane and stirred for 1 hour s. The ethanol was removed in vacuo
and the clear oil was triturated with ether/dichloromethane to give
(1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride as a white solid. MS (ES) m/z 299.0
Example 119
(1S,2R)-1-(5-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol Hydrochloride
##STR00125##
[1188] In an analogous manner to EXAMPLE 117, step 1 ethyl
5-chloro-3-methyl-1H-indole-2-carboxylate was prepared from
4-chloro-phenylamine. MS (ES) m/z 235.9
[1189] In an analogous manner to EXAMPLE 117, step 2
5-chloro-3-methyl-1H-indole-2-carboxylic acid was prepared from
ethyl 5-chloro-3-methyl-1H-indole-2-carboxylate. MS (ESI) m/z
208
[1190] In an analogous manner to EXAMPLE 117, step 3
5-chloro-3-methyl-1H-indole was prepared from
5-chloro-3-methyl-1H-indole-2-carboxylic acid. MS (ESI) m/z
166.
[1191] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
was prepared from 5-chloro-3-methyl-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ES) m/z 316.0
[1192] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(5-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol hydrochloride was prepared from
(2S,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol.
MS (ES) m/z 329.0
Example 120
(1S,2R)-3-amino-1-(5-chloro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00126##
[1194] In an analogous mannerto EXAMPLE 118,
(1S,2R)-3-amino-1-(5-chloro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
was prepared from
(2S,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
(EXAMPLE 119, step 4). MS (ES) m/z 315.1
Example 121
[(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]meth-
ylamine
##STR00127##
[1196] A mixture of (2S,3S)-toluene-4-sulfonic acid
3-(5-chloro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester
(Intermediate in EXAMPLE 119, step 6, 0.52 g, 1.1 mmol),
trifluoro-methanesulfonic acid methyl ester (0.6 mL, 5.5 mmol), and
2,6-di-tert-butyl-4-methyl-pyridine (1.1 g, 5.5 mmol) was heated at
reflux in dichloromethane (20 mL) for 2 hours. The reaction was
partitioned between ethyl acetate (25 mL) and a 1N aqueous solution
of hydrochloric acid (25 mL). The organics were separated and
washed with a saturated aqueous solution of sodium bicarbonate (25
mL), dried over anhydrous sodium sulfate, and concentrated in
vacuo. The crude product was purified via flash column
chromatography (silica, 20% ethyl acetate in hexane) to give
(2S,3S)-toluene-4-sulfonic acid
3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester.
To a solution of toluene-4-sulfonic acid
3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester
(0.13 g, 0.27 mmol) in methanol (10 mL) was added a 2N solution of
methylamine in methanol (1.4 mL, 2.7 mmol) and the reaction heated
in a sealed tube for 12 hours. Upon completion, the reaction was
partitioned between a saturated aqueous solution sodium bicarbonate
(25 mL) and dichloromethane (25 mL). The organics were separated
and removed in vacuo. The residue was taken up in diethyl ether (25
mL) and washed with a 1N aqueous solution of hydrochloric acid (25
mL). The aqueous layer was basified to pH 8 with a saturated
aqueous solution of sodium bicarbonate (50 mL). The product was
extracted with diethyl ether (25 mL), dried over anhydrous sodium
sulfate, and concentrated in vacuo. The free base was dissolved in
a minimum amount of ethanol and treated with a 4N solution of
hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol
was removed in vacuo to give
[(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]met-
hylamine as a yellow oil. MS (ESI) m/z 343
Example 122
(1S,2R)-1-(7-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol Hydrochloride
##STR00128##
[1198] In an analogous manner to EXAMPLE 117, step 1 ethyl
7-chloro-3-methyl-1H-indole-2-carboxylate was prepared from
2-chloro-phenylamine. MS (ESI) m/z 238
[1199] In an analogous manner to EXAMPLE 117, step 2
7-chloro-3-methyl-1H-indole-2-carboxylic acid was prepared from
ethyl 7-chloro-3-methyl-1H-indole-2-carboxylate. MS (ES) m/z
208.0
[1200] In an analogous manner to EXAMPLE 117, step 3
7-chloro-3-methyl-1H-indole was prepared from
7-chloro-3-methyl-1H-indole-2-carboxylic acid.
[1201] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(7-chloro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
was prepared from 7-chloro-3-methyl-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 316; MS (ESI) m/z 314.
[1202] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(7-chloro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-chloro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol.
MS (ESI) m/z 329
Example 123
[(2R,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]meth-
ylamine Hydrochloride
##STR00129##
[1204] In an analogous manner to EXAMPLE 121,
[(2R,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]met-
hylamine hydrochloride was prepared (2S,3S)-toluene-4-sulfonic acid
3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester
(Intermediate in EXAMPLE 117, step 6). MS (ESI) m/z 327.
Example 124
(1S,2R)-1-(4-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00130##
[1206] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(4-bromo-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 4-bromo-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 346.
[1207] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(4-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(4-bromo-1H-indol-1-yl)-3-phenylpropane-1,2-diol. MS
(ESI) m/z 359.
Example 125
(1S,2R)-1-(4-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-
-2-ol Hydrochloride
##STR00131##
[1209] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(4-bromo-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 4-bromo-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step
3). MS (ESI) m/z 364.
[1210] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(4-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol hydrochloride was prepared from
(2S,3S)-3-(4-bromo-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol.
MS (ESI) m/z 377.
Example 126
(1S,2R)-1-(5-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00132##
[1212] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(5-bromo-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 5-bromo-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 346.
[1213] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(5-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(5-bromo-1H-indol-1-yl)-3-phenylpropane-1,2-diol. MS
(ESI) m/z 359.
Example 127
(1S,2R)-1-(5-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-
-2-ol Hydrochloride
##STR00133##
[1215] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(5-bromo-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 5-bromo-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step
3). MS (ESI) m/z 364.
[1216] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(5-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol hydrochloride was prepared from
(2S,3S)-3-(5-bromo-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol.
MS (ESI) m/z 377.
Example 128
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-4-carbonitr-
ile Hydrochloride
##STR00134##
[1218] In an analogous manner to EXAMPLE 117, step 5
1-(2,3-dihydroxy-1-phenyl-propyl)-1H-indole-4-carbonitrile was
prepared from 1H-Indole-4-carbonitrile and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4).
[1219] In an analogous manner to EXAMPLE 117, step 6
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-4-carbonit-
rile hydrochloride was prepared from
1-(2,3-dihydroxy-1-phenyl-propyl)-1H-indole-4-carbonitrile. MS
(ESI) m/z 306.
Example 129
(1S,2R)-1-(6-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00135##
[1221] In an analogous manner to EXAMPLE 117, step 5
3-(6-bromo-indol-1-yl)-3-phenyl-propane-1,2-diol was prepared from
6-bromo-1H-indole and [(2R,3R)-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4).
[1222] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(6-bromo-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
3-(6-bromo-indol-1-yl)-3-phenyl-propane-1,2-diol. MS (ESI) m/z
359
Example 130
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-5-carbonitr-
ile Hydrochloride
##STR00136##
[1224] In an analogous manner to EXAMPLE 117, step 5
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1H-indole-5-carbonitrile
was prepared from 1H-Indole-5-carbonitrile and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 293
[1225] In an analogous manner to EXAMPLE 117, step 6
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1H-indole-5-carbonit-
rile hydrochloride was prepared from
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1H-indole-5-carbonitrile.
MS (ES) m/z 306.1.
Example 131
1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1H-indole-4-
-carbonitrile Hydrochloride
##STR00137##
[1227] In an analogous manner to EXAMPLE 117, step 5
1-[1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-1H-indole-4-carbonitrile
was prepared from 1H-Indole-4-carbonitrile and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step
3).
[1228] In an analogous manner to EXAMPLE 117, step 6
1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1H-indole--
4-carbonitrile hydrochloride was prepared from
1-[1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-1H-indole-4-carbonitrile.
MS (ES) m/z 324.2.
Example 132
(1S,2R)-1-(6-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-
-2-ol Hydrochloride
##STR00138##
[1230] In an analogous manner to EXAMPLE 117, step 5
3-(6-bromo-indol-1-yl)-3-(3-fluoro-phenyl)-propane-1,2-diol was
prepared from 6-bromo-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step
3).
[1231] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(6-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol hydrochloride was prepared from
3-(6-bromo-indol-1-yl)-3-(3-fluoro-phenyl)-propane-1,2-diol. MS
(ES) m/z 377.1.
Example 133
(1S,2R)-1-(6-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00139##
[1233] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(6-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 6-fluoro-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step
3). MS (ESI) m/z 304.
[1234] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(6-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(6-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol.
MS (ES) m/z 317.1.
Example 134
(1S,2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol
Hydrochloride
##STR00140##
[1236] In an analogous manner to EXAMPLE 117, step 5
3-(3-fluoro-phenyl)-3-indol-1-yl-propane-1,2-diol was prepared from
1H-indole and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol
(EXAMPLE 47, step 3).
[1237] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol
hydrochloride was prepared from
3-(3-fluoro-phenyl)-3-indol-1-yl-propane-1,2-diol and
para-toluenesulfonic acid followed by concentrated ammonium
hydroxide. MS (ES) m/z 285.2.
Example 135
(1S,2R)-1-(7-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-
-2-ol Hydrochloride
##STR00141##
[1239] In an analogous manner to EXAMPLE 117, step 5
3-(7-bromo-indol-1-yl)-3-(3-fluoro-phenyl)-propane-1,2-diol was
prepared from 7-bromo-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47 step
3).
[1240] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(7-bromo-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol hydrochloride was prepared from
3-(7-bromo-indol-1-yl)-3-(3-fluoro-phenyl)-propane-1,2-diol. MS
(ES) m/z 377.
Example 136
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl)phenyl]pro-
pan-2-ol Hydrochloride
##STR00142##
[1242] In an analogous manner to EXAMPLE 47, step 1 cinnamic acid,
m-(trifluoromethyl)-, methyl ester was prepared from
3-(3-trifluoromethyl-phenyl)-acrylic acid. MS (ES) m/z 231.1
[1243] In an analogous manner to EXAMPLE 47, step 2
(2E)-3-[3-[trifluoromethyl)phenyl]prop-2-en-1-ol was prepared from
cinnamic acid, m-(trifluoromethyl)-, methyl ester. MS (ES) m/z
185.1
[1244] In an analogous manner to EXAMPLE 47, step 3
{(2R,3R)-3-[3-(trifluoromethyl)phenyl]oxiran-2-yl}methanol was
prepared from (2E)-3-[3-[trifluoromethyl)phenyl]prop-2-en-1-ol. MS
(ES) m/z 217.3
[1245] In an analogous manner to EXAMPLE 47, step 4
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-[3-(trifluoromethyl)phenyl]propan-
e-1,2-diol was prepared from indoline and
{(2R,3R)-3-[3-(trifluoromethyl)phenyl]oxiran-2-yl}methanol. MS
(ESI) m/z 338.
[1246] In an analogous manner to EXAMPLE 47, step 5
(2S,3S)-3-(1H-indol-1-yl)-3-[3-(trifluoromethyl)phenyl]propane-1,2-diol
was prepared from
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-[3-(trifluoromethyl)phenyl]propan-
e-1,2-diol. MS (ESI) m/z 336.
[1247] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl)phenyl]pr-
opan-2-ol hydrochloride was prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-[3-(trifluoromethyl)phenyl]propane-1,2-diol.
MS (ES) m/z 349.1.
Example 137
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclohexane-1,3'-indol]-
-1'(2'H)-ylpropan-2-ol Hydrochloride
##STR00143##
[1249] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-spiro[cyclohexane-1,3'-indol]-1
'(2'H)-ylpropane-1,2-diol was prepared from
1',2'-dihydrospiro[cyclohexane-1,3'-indole].sup.15 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a white solid. MS (ES) m/z 356.2 ([M+H].sup.+); HRMS: calcd
for C.sub.22H.sub.26FNO.sub.2+H.sup.+, 356.2020; found (ESI,
[M+H].sup.+), 356.2031. .sup.15Kucerovy, A.; Hathaway, J. S.;
Mattner, P. G.; Repic, O, Synth. Commun. 1992, 22, 729-733.
[1250] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclohexane-1,3'-indol-
]-1 '(2'H)-ylpropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-spiro[cyclohexane-1,3'-indol]-1'(2'H)-ylprop-
ane-1,2-diol as a white powder. MS (ES) m/z 369.2 ([M+H].sup.+);
HRMS: calcd for C.sub.23H.sub.29FN.sub.2O+H.sup.+, 369.2337; found
(ESI, [M+H]+), 369.2332.
Example 138
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluoromethy-
l)phenyl]propan-2-ol Hydrochloride
##STR00144##
[1252] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-[3-(trifluorometh-
yl)phenyl]propan-2-ol was prepared from
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-[3-(trifluoromethyl)phenyl]propan-
e-1,2-diol (EXAMPLE 136, step 4). MS (ES) m/z 351.1.
Example 139
(1S,2S)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
Hydrochloride
##STR00145##
[1254] In an analogous manner to EXAMPLE 16, step 2
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-nitrobenzoate was prepared from
3-(3-fluoro-phenyl)-3-indol-1-yl-propane-1,2-diol (EXAMPLE 134,
step 1). MS (ES) m/z 435.0.
[1255] In an analogous manner to EXAMPLE 16, step 3 4-nitro-benzoic
acid 3-(3-fluoro-phenyl)-3-indol-1-yl-2-methanesulfonyloxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl
4-nitrobenzoate.
[1256] In an analogous manner to EXAMPLE 16, step 4
1-{(S)-(3-fluorophenyl)[(2R)-oxiran-2-yl]methyl}-1H-indole was
prepared from 4-nitro-benzoic acid
3-(3-fluoro-phenyl)-3-indol-1-yl-2-methanesulfonyloxy-propyl ester.
MS (ESI) m/z 338.
[1257] In an analogous manner to EXAMPLE 16, step 5
(1S,2S)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol
hydrochloride was prepared from
1-{(S)-(3-fluorophenyl)[(2R)-oxiran-2-yl]methyl}-1H-indole. MS
(ESI) m/z 299.
Example 140
(1S,2R)-1-(3,4-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-o-
l Hydrochloride
##STR00146##
[1259] In an analogous manner to EXAMPLE 47, step 1 cinnamic acid,
3,4-difluoro-, methyl ester, (E) was prepared from
3-(3,4-difluoro-phenyl)-acrylic acid. MS (ES) m/z 199.1
[1260] In an analogous manner to EXAMPLE 47, step 2
(2E)-3-(3,4-difluorophenyl)prop-2-en-1-ol was prepared from
cinnamic acid, 3,4-difluoro-, methyl ester, (E). MS (ES) m/z
153.1
[1261] In an analogous manner to EXAMPLE 47, step 3
[(2R,3R)-3-(3,4-difluorophenyl)oxiran-2-yl]methanol was prepared
from (2E)-3-(3,4-difluorophenyl)prop-2-en-1-ol. MS (ES) m/z
185.1
[1262] In an analogous manner to EXAMPLE 47, step 4
(2S,3S)-3-(3,4-difluorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-d-
iol was prepared from indoline and
[(2R,3R)-3-(3,4-difluorophenyl)oxiran-2-yl]methanol. MS (ES) m/z
306.1.
[1263] In an analogous manner to EXAMPLE 47, step 5
(2S,3S)-3-(3,4-difluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol
was prepared from
(2S,3S)-3-(3,4-difluorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-d-
iol. MS (ESI) m/z 304.
[1264] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(3,4-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2--
ol hydrochloride was prepared from
(2S,3S)-3-(3,4-difluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol.
MS (ES) m/z 317.1.
Example 141
(1RS,2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)--
1-phenylpropan-2-ol Hydrochloride
##STR00147##
[1266] In an analogous manner to EXAMPLE 33, step 1, ethyl
(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phe-
nylpropanoate was prepared from
6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 88, step 1) and
trans-ethyl-3-phenylglycidate as a viscous, yellow liquid. MS (ESI)
m/z 362.0 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.20ClNO.sub.4+H.sup.+, 362.1154; found (ESI,
[M+H].sup.+), 362.1150.
[1267] In an analogous manner to EXAMPLE 33, step 2,
(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-met-
hyl-3-phenylpropanamide was prepared from ethyl (2RS,3
RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpro-
panoate as white needles. MS (ESI) m/z 344.9 ([M-H].sup.-); HRMS:
calcd for C.sub.18H.sub.19ClN.sub.2O.sub.3+H.sup.+, 347.1157; found
(ESI, [M+H].sup.+), 347.1150.
[1268] In an analogous manner to EXAMPLE 33, step 3,
(1RS,2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-
-1-phenylpropan-2-ol hydrochloride was prepared from
(2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-met-
hyl-3-phenylpropanamide as a white powder. MS (ESI) m/z 333.1
([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.21ClN.sub.2O.sub.2+H.sup.+, 333.1370; found (ESI,
[M+H].sup.+), 333.1381.
Example 142
(1RS,2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)--
1-phenylpropan-2-ol Hydrochloride
##STR00148##
[1270] In an analogous manner to EXAMPLE 165, step
1,6-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from
6-methyl-2H-1,4-benzoxazin-3(4H)-one as a yellow oil. MS (ES) m/z
150.0 ([M+H].sup.+); HRMS: calcd for C.sub.9H.sub.11NO+H.sup.+,
150.0919; found (ESI, [M+H].sup.+), 150.0924.
[1271] In an analogous manner to EXAMPLE 33, step 1, ethyl
(2RS,3RS)-2-hydroxy-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phe-
nylpropanoate was prepared from
6-methyl-3,4-dihydro-2H-1,4-benzoxazine and
trans-ethyl-3-phenylglycidate as a viscous, yellow liquid. MS (ESI)
m/z 342.0 ([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.23NO.sub.4+H.sup.+, 342.1700; found (ESI,
[M+H].sup.+), 342.1683.
[1272] In an analogous manner to EXAMPLE 33, step 2,
(2RS,3RS)-2-hydroxy-N-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4--
yl)-3-phenylpropanamide was prepared from ethyl (2 RS,3
RS)-2-hydroxy-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpro-
panoate as a white powder. MS (ESI) m/z 325.0 ([M-H].sup.-); HRMS:
calcd for C.sub.19H.sub.22N.sub.2O.sub.3+H.sup.+, 327.1703; found
(ESI, [M+H].sup.+), 327.1703.
[1273] In an analogous manner to EXAMPLE 33, step 3,
(1RS,2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-
-1-phenylpropan-2-ol hydrochloride was prepared from
(2RS,3RS)-2-hydroxy-N-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4--
yl)-3-phenylpropanamide as a white powder. MS (ESI) m/z 313.0
([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.24N.sub.2O.sub.2+H.sup.+, 313.1911; found (ESI,
[M+H].sup.+), 313.1908.
Example 143
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)propa-
n-2-ol Hydrochloride
##STR00149##
[1275] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(3-fluorophenyl)-3-(3-methyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 3-methylindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish oil. MS (ES) m/z 300.0 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.18FNO.sub.2+H.sup.+, 300.1400; found
(ESI, [M+H]+), 300.1400.
[1276] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-1H-indol-1-yl)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-methyl-1H-indol-1-yl)propane-1,2-diol
as a white solid. MS (ES) m/z 313.0 ([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.21FN.sub.2O+H.sup.+, 313.1711; found (ESI,
[M+H].sup.+), 313.1713.
Example 144
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1--
phenylpropan-2-ol Hydrochloride
##STR00150##
[1278] Step 1: Racemic
(1RS,2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-
-1-phenylpropan-2-ol (EXAMPLE 141) was dissolved in methanol. The
resulting solution was injected onto the Supercritical Fluid
Chromatography instrument. The baseline resolved enantiomers, using
the conditions described below, were collected. The enantiomeric
purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralpak
AD-H 5u, 250 mm.times.4.6 mm ID column at 2.0 mL/minutes flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del. USA). [1279] SFC Instrument: Berger
MultiGram Prep SFC (Berger Instruments, Inc. Newark, Del. 19702.
[1280] Column: Chiralpak AD-H; 5u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa., USA) [1281] Column temperature:
35.degree. C. [1282] SFC Modifier: 40% MeOH with 0.5% DEA [1283]
Flow rate: 50 mL/min [1284] Outlet Pressure: 100 bar [1285]
Detector: UV at 266 nm
[1286] Step 2: A solution of
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-
-phenylpropan-2-ol, isolated as Peak 1, (58 mg, 0.17 mmol) in
dichloromethane (3 mL) was treated with an ethereal solution of
hydrochloric acid (1 M, 0.2 mL, 0.2 mmol). To the resulting
solution was added hexane until white powder formed, which was
collected, washed with hexane, and dried in vacuo to yield 62 mg
(45%) of
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-
-phenylpropan-2-ol hydrochloride. Chiral purity: >99.9%. MS
(ESI) m/z 333.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.21ClN.sub.2O.sub.2+H.sup.+, 333.1370; found (ESI,
[M+H].sup.+), 333.1372.
Example 145
(1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1--
phenylpropan-2-ol Hydrochloride
##STR00151##
[1288] In an analogous manner to EXAMPLE 144, step 2,
(1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-
-phenylpropan-2-ol hydrochloride was prepared from
(1R,2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-
-phenylpropan-2-ol which was isolated as Peak 2 of the chiral
separation (EXAMPLE 144, step 1). Chiral purity: >99.9%. MS
(ESI) m/z 333.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.21ClN.sub.2O.sub.2+H.sup.+, 333.1370; found (ESI,
[M+H].sup.+), 333.1374.
Example 146
(1S,2R)-1-(4-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00152##
[1290] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(4-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 4-chloroindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, yellowish oil. MS (ES) m/z 300.0 ([M-H].sup.-).
[1291] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(4-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(4-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white powder. MS (ES) m/z 315.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19ClN.sub.2O+H.sup.+, 315.1259; found (ESI,
[M+H].sup.+), 315.1255.
Example 147
(1S,2R)-1-(6-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00153##
[1293] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(6-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 6-chloroindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, colorless oil. MS (ES) m/z 302.0 ([M+H].sup.+); HRMS:
calcd for C.sub.17H.sub.16ClNO.sub.2+H.sup.+, 302.0948; found (ESI,
[M+H].sup.+), 302.0946.
[1294] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(6-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(6-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white powder. MS (ES) m/z 315.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19ClN.sub.2O+H.sup.+, 315.1259; found (ESI, [M+H]+),
315.1263.
Example 148
(1S,2R)-1-(7-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00154##
[1296] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(7-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 7-chloroindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, colorless oil. MS (ES) m/z 302.0 ([M+H].sup.+); HRMS:
calcd for C.sub.17H.sub.16ClNO.sub.2+H.sup.+, 302.0948; found (ESI,
[M+H].sup.+), 302.0949.
[1297] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(7-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(7-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white powder. MS (ES) m/z 315.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19ClN.sub.2O+H.sup.+, 315.1259; found (ESI,
[M+H].sup.+), 315.1269.
Example 149
(1S,2R)-1-(7-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00155##
[1299] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(7-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 7-chloroindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 320.0 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.15ClFNO.sub.2+H.sup.+, 320.0848;
found (ESI, [M+H].sup.+), 320.0858.
[1300] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(7-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a white powder. MS (ES) m/z 333.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.18ClFN.sub.2O+H.sup.+, 333.1170; found (ESI,
[M+H].sup.+), 333.1189.
Example 150
(1S,2R)-1-(4-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00156##
[1302] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(4-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 4-chloroindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 320.0 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.15ClFNO.sub.2+H.sup.+, 320.0848;
found (ESI, [M+H].sup.+), 320.0856.
[1303] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(4-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(4-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a white powder. MS (ES) m/z 333.2 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.18ClFN.sub.2O+H.sup.+, 333.1170; found (ESI,
[M+H].sup.+), 333.1156.
Example 151
(1S,2R)-1-(6-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00157##
[1305] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(6-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 6-chloroindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 320.0 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.15ClFNO.sub.2+H.sup.+, 320.0848;
found (ESI, [M+H].sup.+), 320.0855.
[1306] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(6-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(6-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a white powder. MS (ES) m/z 333.2 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.18ClFN.sub.2O+H.sup.+, 333.1170; found (ESI,
[M+H].sup.+), 333.1174.
Example 152
(1S,2R)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00158##
[1308] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(5-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 5-chloroindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, colorless oil. MS (ES) m/z 302.2 ([M+H].sup.+); HRMS:
calcd for C.sub.17H.sub.16ClNO.sub.2+H.sup.+, 302.0948; found (ESI,
[M+H].sup.+), 302.0956.
[1309] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(5-chloro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(5-chloro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white powder. MS (ES) m/z 315.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.19ClN.sub.2O+H.sup.+, 315.1259; found (ESI,
[M+H].sup.+), 315.1247.
Example 153
(1S,2R)-1-(5-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00159##
[1311] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(5-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 5-chloroindole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, colorless oil. MS (ES) m/z 320.1 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.15ClFNO.sub.2+H.sup.+, 320.0848;
found (ESI, [M+H].sup.+), 320.0854.
[1312] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(5-chloro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
2S,3S)-3-(5-chloro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a white powder. MS (ES) m/z 333.1 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.18ClFN.sub.2O+H.sup.+, 333.1170; found (ESI,
[M+H].sup.+), 333.1154.
Example 154
(1S,2R)-1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00160##
[1314] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(3-isopropyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 3-isopropylindole.sup.16 and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, yellowish oil. HRMS: calcd for
C.sub.20H.sub.23NO.sub.2+H+, 310.1802; found (ESI, [M+H]+),
310.1793. .sup.16Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L.
S. J. Org. Chem. 1980, 45, 2709-2710.
[1315] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(3-isopropyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white powder. MS (ES) m/z 323.3 ([M+H].sup.+); HRMS: calcd for
C.sub.21H.sub.26N.sub.2O+H.sup.+, 323.2118; found (ESI,
[M+H].sup.+), 323.2117.
Example 155
(1S,2R)-1-(3-fluorophenyl)-1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)pr-
opan-2-ol Hydrochloride
##STR00161##
[1317] In an analogous manner to EXAMPLE 117, step 5,
(2S,3S)-3-(3-fluorophenyl)-3-(3-isopropyl-1H-indol-1-yl)propane-1,2-diol
was prepared from 3-isopropylindole.sup.16 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish oil. MS (ES) m/z 326.2 ([M-H].sup.-);
HRMS: calcd for C.sub.20H.sub.22FNO.sub.2+H.sup.+, 328.1707; found
(ESI, [M+H]+), 328.1709.
[1318] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-1-(3-isopropyl-1H-indol-1-yl)-3-(methylamino)p-
ropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-isopropyl-1H-indol-1-yl)propane-1,2-diol
as a white powder. MS (ES) m/z 341.3 ([M+H].sup.+); HRMS: calcd for
C.sub.21H.sub.25FN.sub.2O+H.sup.+, 341.2024; found (ESI,
[M+H].sup.+), 341.2025.
Example 156
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-
-3-(methylamino)propan-2-ol Hydrochloride
##STR00162##
[1320] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluorophenyl-
)propane-1,2-diol was prepared from
6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 88, step 1) and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish liquid. MS (ES) m/z 335.8 ([M-H].sup.-);
HRMS: calcd for C.sub.20H.sub.22FNO.sub.2+H.sup.+, 338.0959; found
(ESI, [M+H].sup.+), 338.0959.
[1321] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl-
)-3-(methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluorophenyl-
)propane-1,2-diol as a white powder. MS (ES) m/z 351.0
([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.20ClFN.sub.2O.sub.2+H.sup.+, 351.1276; found (ESI,
[M+H].sup.+), 351.1276.
Example 157
(1S,2R)-1-(3,5-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-o-
l Hydrochloride
##STR00163##
[1323] Step 1: In an analogous manner to EXAMPLE 47, step 1,
trans-3,5-difluorocinnamic acid methyl ester was prepared from
trans-3,5-difluorocinnamic acid as a white solid. MS (ESI) m/z
198.0; HRMS: calcd for C.sub.10H.sub.8F.sub.2O.sub.2, 198.0492;
found (ESI, [M].sup.+), 198.0489.
[1324] Step 2: In an analogous manner to EXAMPLE 47, step 2,
trans-3,5-difluorocinnamyl alcohol was prepared from
trans-3,5-difluorocinnamic acid methyl ester as a colorless
oil.
[1325] Step 3: In an analogous manner to EXAMPLE 47, step 3,
[(2R,3R)-3-(3,5-difluorophenyl)oxiran-2-yl]methanol was prepared
from trans-3,5-difluorocinnamyl alcohol as a colorless liquid.
Percent ee: 97.9%. MS (ESI) m/z 186.0; HRMS: calcd for
C.sub.9H.sub.8F.sub.2O.sub.2, 186.0492; found (ESI, [M].sup.+),
186.0501.
[1326] Step 4: In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3,5-difluorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-d-
iol was prepared from indoline and
[(2R,3R)-3-(3,5-difluorophenyl)oxiran-2-yl]methanol as a viscous,
yellowish oil. MS (ES) m/z 306.2 ([M+H].sup.+); HRMS: calcd for
C.sub.17H.sub.17F.sub.2NO.sub.2+H.sup.+, 306.1300; found (ESI,
[M+H].sup.+), 306.1299.
[1327] Step 5: In an analogous manner to EXAMPLE 47, step 5,
(2S,3S)-3-(3,5-difluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol
was prepared from
(2S,3S)-3-(3,5-difluorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-d-
iol as a viscous, yellowish oil. MS (ES) m/z 304.0 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.15F.sub.2NO.sub.2+H.sup.+, 304.1144;
found (ESI, [M+H].sup.+), 304.1146.
[1328] Step 6: In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3,5-difluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2--
ol hydrochloride was prepared from
(2S,3S)-3-(3,5-difluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol as
a white powder. MS (ES) m/z 317.0 ([M+H].sup.+); HRMS: calcd for
C.sub.18H.sub.18F.sub.2N.sub.2O+H.sup.+, 317.1465; found (ESI,
[M+H].sup.+), 317.1465.
Example 158
(1S,2R)-1-(3,5-difluorophenyl)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylamin-
o)propan-2-ol Hydrochloride
##STR00164##
[1330] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3,5-difluorophenyl)-1-(2,3-dihydro-1H-indol-1-yl)-3-(methylami-
no)propan-2-ol was prepared from
(2S,3S)-3-(3,5-difluorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-d-
iol as a white powder. MS (ES) m/z 319.0 ([M+H].sup.+); HRMS: calcd
for C.sub.18H.sub.20F.sub.2N.sub.2O+H.sup.+, 319.1622; found (ESI,
[M+H].sup.+), 319.1622.
Example 159
(1S,2R)-4-amino-1-(3-fluorophenyl)-1-(1H-indol-1-yl)butan-2-ol
Hydrochloride
##STR00165##
[1332] In an analogous manner to Example 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-2-hydroxy-3-indol-1-yl-propyl ester was prepared
from (2S,3S)-3-(3-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol
(Example 47, step 4). MS (ES) m/z 440 ([M+H].sup.+).
Example 160
(1S,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(m-
ethylamino)propan-2-ol Hydrochloride
##STR00166##
[1334] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)prop-
ane-1,2-diol was prepared from 3,3-dimethylindoline.sup.15 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, brown liquid. MS (ES) m/z 316.0 ([M+H].sup.+);
HRMS: calcd for C.sub.19H.sub.22FNO.sub.2+H.sup.+, 316.1713; found
(ESI, [M+H].sup.+), 316.1713.
[1335] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(-
methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)prop-
ane-1,2-diol as a white powder. MS (ES) m/z 329.0
([M+H].sup.+).
Example 161
(1S,2R)-1-(3,5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)--
3-(methylamino)propan-2-ol Hydrochloride
##STR00167##
[1337] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3,5-difluorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
propane-1,2-diol was prepared from 3,3-dimethylindoline.sup.15 and
[(2R,3R)-3-(3,5-difluorophenyl)oxiran-2-yl]methanol (EXAMPLE 157,
step 3) as a viscous, brown liquid. MS (ES) m/z 334.0
([M+H].sup.+); HRMS: calcd for
C.sub.19H.sub.21F.sub.2NO.sub.2+H.sup.+, 334.1619; found (ESI,
[M+H].sup.+), 334.1619.
[1338] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3,5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
-3-(methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3,5-difluorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
propane-1,2-diol as a white powder. MS (ES) m/z 347.0
([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.24F.sub.2N.sub.2O+H.sup.+, 347.1929; found (ESI,
[M+H].sup.+), 347.1929.
Example 162
(1S,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-pheny-
lpropan-2-ol Hydrochloride
##STR00168##
[1340] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-di-
ol was prepared from 3,3-dimethylindoline.sup.15 and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
viscous, brown liquid. MS (ES) m/z 298.0 ([M+H].sup.+); HRMS: calcd
for C.sub.19H.sub.23NO.sub.2+H.sup.+, 298.1807; found (ESI,
[M+H].sup.+), 298.1807.
[1341] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methylamino)-1-phen-
ylpropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-di-
ol as a white powder. MS (ES) m/z 311.0 ([M+H].sup.+); HRMS: calcd
for C.sub.20H.sub.26N.sub.2O+H.sup.+, 311.2118; found (ESI,
[M+H].sup.+), 311.2107.
Example 163
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indo-
l-1-yl)propan-2-ol Hydrochloride
##STR00169##
[1343] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-(3-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol was prepared from 3-methylindoline.sup.4 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish liquid. MS (ES) m/z 301.8 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.20FNO.sub.2+H.sup.+, 302.1551; found
(ESI, [M+H].sup.+), 302.1539.
[1344] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-ind-
ol-1-yl)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-methyl-2,3-dihydro-1H-indol-1-yl)propane--
1,2-diol as a white powder. MS (ES) m/z 315.2 ([M+H].sup.+); HRMS:
calcd for C.sub.19H.sub.23FN.sub.2O+H.sup.+, 315.1873; found (ESI,
[M+H].sup.+), 315.1881.
Example 164
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclopentane-1,3'-indol-
]-1 '(2'H)-ylpropan-2-ol Hydrochloride
##STR00170##
[1346] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-spiro[cyclopentane-1,3'-indol]-1'(2'H)-ylpro-
pane-1,2-diol was prepared from
1',2'-dihydrospiro[cyclopentane-1,3'-indole].sup.15 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish liquid. MS (ES) m/z 342.2
([M+H].sup.+).
[1347] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiro[cyclopentane-1,3'-indo-
l]-1 '(2'H)-ylpropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-spiro[cyclopentane-1,3'-indol]-1'(2'H)-ylpro-
pane-1,2-diol as a white powder. MS (ES) m/z 355.0 ([M+H].sup.+);
HRMS: calcd for C.sub.22H.sub.27FN.sub.2O+H.sup.+, 355.2180; found
(ESI, [M+H].sup.+), 355.2178.
Example 165
(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophe-
nyl)-3-(methylamino)propan-2-ol Hydrochloride
##STR00171##
[1349] Step 1: To a solution of
2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one.sup.17 (2.658 g, 15.0
mmol) in tetrahydrofuran (10 mL) under nitrogen was added slowly a
solution of borane (1.0 M in tetrahydrofuran, 22.5 mL, 22.5 mmol)
via a syringe. The resulting mixture was stirred at room
temperature for 10 minutes and then at 70.degree. C. for 1 hour s.
After cooling, the reaction mixture was quenched with methanol (3
mL) slowly. All volatiles were removed under reduced pressure. A 1
N aqueous solution of hydrochloric acid (10 mL) was added to the
liquid residue and the mixture was warmed to 50.degree. C. for 10
minutes. After cooling, the reaction mixture was made alkaline
using saturated sodium bicarbonate solution (15 mL), and extracted
with ethyl acetate (25 mL). The organic layer was washed with
water, brine, dried (anhydrous sodium sulfate), filtered through a
pad of silica gel, and concentrated under reduced pressure to yield
2.310 g (94%) of 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine as a
brown oil. MS (ES) m/z 164.0 ([M+H].sup.+). .sup.17Caliendo, G.;
Perissutti, E.; Santagada, V.; Fiorino, F.; Severino, B.; Bianca,
R.
[1350] Step 2: In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluoroph-
enyl)propane-1,2-diol was prepared from
2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a white solid. MS (ES) m/z 332.2 ([M+H].sup.+); HRMS: calcd
for C.sub.19H.sub.22FNO.sub.3+H.sup.+, 332.1657; found (ESI,
[M+H].sup.+), 332.1648.
[1351] Step 3: In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluoroph-
enyl)-3-(methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluoroph-
enyl)propane-1,2-diol as a white powder. MS (ES) m/z 345.2
([M+H].sup.+); HRMS: calcd for
C.sub.20H.sub.25FN.sub.2O.sub.2+H.sup.+, 345.1978; found (ESI,
[M+H].sup.+), 345.1981.
Example 166
(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino-
)-1-phenylpropan-2-ol Hydrochloride
##STR00172##
[1353] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropa-
ne-1,2-diol was prepared from
2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 165, step 1)
and [(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as
a white solid. MS (ES) m/z 314.1 ([M+H].sup.+).
[1354] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamin-
o)-1-phenylpropan-2-ol hydrochloride was prepared from
(2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropa-
ne-1,2-diol as a white powder. MS (ES) m/z 327.2 ([M+H].sup.+);
HRMS: calcd for C.sub.20H.sub.26N.sub.2O.sub.2+H.sup.+, 327.2073;
found (ESI, [M+H].sup.+), 327.2082.
Example 167
(1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(met-
hylamino)propan-2-ol Hydrochloride
##STR00173##
[1356] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-3-(3-fluorophenyl)propan-
e-1,2-diol was prepared from
3,4-dihydro-2H-1,4-benzothiazine.sup.18 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish liquid. MS (ES) m/z 320.1 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.18FN02S+H.sup.+, 320.1115; found
(ESI, [M+H]+), 320.1113. .sup.18El-Subbagh, H. I.; Abadi, A. H.;
Al-Khawad, I.E.; Al-Rashood, K. A. Arch. Pharm. 1999, 332,
19-24.
[1357] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-3-(3-fluorophenyl)propan-
e-1,2-diol as a white powder. MS (ES) m/z 333.1 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.21FN.sub.2OS+H.sup.+, 333.1431; found
(ESI, [M+H].sup.+), 333.1420.
Example 168
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4--
benzoxazin-4-yl)propan-2-ol Hydrochloride
##STR00174##
[1359] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3-fluorophenyl)-3-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl-
)propane-1,2-diol was prepared from
2-phenyl-3,4-dihydro-2H-1,4-benzoxazine.sup.19 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a white solid. MS (ES) m/z 380.0 ([M+H].sup.+); HRMS: calcd
for C.sub.23H.sub.22FNO.sub.3+H.sup.+, 380.1662; found (ESI,
[M+H].sup.+), 380.1661. .sup.19 Olagbemiro, T. O.; Nyakutse, C. A.;
Lajide, L.; Agho, M. O.; Chukwu, C. E. Bull. Soc. Chim. Belg. 1987,
96, 473-480.
[1360] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-
-benzoxazin-4-yl)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl-
)propane-1,2-diol as a white powder. MS (ES) m/z 393.2
([M+H].sup.+); HRMS: calcd for
C.sub.24H.sub.25FN.sub.2O.sub.2+H.sup.+, 393.1978; found (ESI,
[M+H].sup.+), 393.1986.
Example 169
(1S,2R)-1-(3-fluorophenyl)-1-[3-(4-methoxyphenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol Hydrochloride
##STR00175##
[1362] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-methoxyphenyl]-1H-indol-1-yl}propane-1-
,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 4-methoxybenzeneboronic acid.
[1363] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-methoxyphenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-methoxyphenyl]-1H-indol-1-yl}propane-1-
,2-diol.
[1364] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-1-[3-(4-methoxyphenyl)-1H-indol-1-yl]-3-(methy-
lamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-methoxyphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
405.
Example 170
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-methylphenyl)-1H-indol--
1-yl]propan-2-ol Hydrochloride
##STR00176##
[1366] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-methylphenyl]-1H-indol-1-yl}propane-1,-
2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 4-methylbenzeneboronic acid.
[1367] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-methylphenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-methylphenyl]-1H-indol-1-yl}propane-1,-
2-diol.
[1368] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-methylphenyl)-1H-indol-
-1-yl]propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-methylphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
389.2.
Example 171
(1S,2R)-1-[3-(4-tert-butylphenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(met-
hylamino)propan-2-ol Hydrochloride
##STR00177##
[1370] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-tert-butylphenyl]-1H-indol-1-yl}propan-
e-1,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 4-tert-butylphenylboronic acid.
[1371] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-tert-butylphenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-tert-butylphenyl]-1H-indol-1-yl}propan-
e-1,2-diol.
[1372] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-[3-(4-tert-butylphenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-tert-butylphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
430.9; HRMS: calcd for C28H31FN2O+H+, 431.24932; found (ESI,
[M+H]+), 431.2516.
Example 172
(1S,2R)-1-(3-fluorophenyl)-1-[3-(3-methoxyphenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol Hydrochloride
##STR00178##
[1374] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-methoxyphenyl]-1H-indol-1-yl}propane-1-
,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 3-methoxybenzeneboronic acid.
[1375] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(3-methoxyphenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-methoxyphenyl]-1H-indol-1-yl}propane-1-
,2-diol.
[1376] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-1-[3-(3-methoxyphenyl)-1H-indol-1-yl]-3-(methy-
lamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(3-methoxyphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
405.1; HRMS: calcd for C25H25FN2O2+H+, 405.19728; found (ESI,
[M+H]+), 405.196.
Example 173
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl)phenyl-
]-1H-indol-1-yl}propan-2-ol Hydrochloride
##STR00179##
[1378] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-(trifluoromethyl)phenyl]-1H-indol-1-yl-
}propane-1,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 4-(trifluoromethyl)benzeneboronic
acid.
[1379] In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(4-(trifluoromethyl)phenyl)-indol-1-yl]-2-hydroxy-
-propyl ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[4-(trifluoromethyl)phenyl]-1H-indol-1-yl-
}propane-1,2-diol.
[1380] In an analogous manner to EXAMPLE 5
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl)pheny-
l]-1H-indol-1-yl}propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluoro-phenyl)-3-[3-(4-(trifluoromethyl)phenyl)-indol-1-yl]-2-hydrox-
y-propyl ester and methylamine (2N solution in methanol). MS (ESI)
m/z 443.1.
Example 174
(1S,2R)-1-(3,5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-3-(m-
ethylamino)propan-2-ol Hydrochloride
##STR00180##
[1382] In an analogous manner to EXAMPLE 47, step 4,
(2S,3S)-3-(3,5-difluorophenyl)-3-(6-fluoro-2,3-dihydro-1H-indol-1-yl)prop-
ane-1,2-diol was prepared from 6-fluoroindoline and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3) as a viscous, yellowish liquid. MS (ES) m/z 324.1 ([M+H].sup.+);
HRMS: calcd for C.sub.17H.sub.16F.sub.3NO.sub.2+H.sup.+, 324.121 1;
found (ESI, [M+H].sup.+), 324.1226.
[1383] In an analogous manner to EXAMPLE 47, step 6,
(1S,2R)-1-(3,5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-3-(-
methylamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3,5-difluorophenyl)-3-(6-fluoro-2,3-dihydro-1H-indol-1-yl)prop-
ane-1,2-diol as a white powder. MS (ES) m/z 337.3 ([M+H].sup.+);
HRMS: calcd for C.sub.18H.sub.19F.sub.3N.sub.2O+H.sup.+, 337.1522;
found (ESI, [M+H].sup.+), 337.1505.
Example 175
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl)phenyl-
]-1H-indol-1-yl}propan-2-ol Hydrochloride
##STR00181##
[1385] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-(trifluoromethyl)phenyl]-1H-indol-1-yl-
}propane-1,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 2-(trifluoromethyl)boronic acid.
[1386] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-2-hydroxy-3-[3-(2-(trifluoromethyl)phenyl)-indol-1-yl]-
-propyl ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-(trifluoromethyl)phenyl]-1H-indol-1-yl-
}propane-1,2-diol.
[1387] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl)pheny-
l]-1H-indol-1-yl}propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-2-hydroxy-3-[3-(2-(trifluoromethyl)phenyl)-indol-1-yl]-
-propyl ester and methylamine (2N solution in methanol). MS (ESI)
m/z 443.1; HRMS: calcd for C25H22F4N2O+H+, 443.17410; found (ESI,
[M+H]+), 443.172.
Example 176
(1S,2R)-1-(3-fluorophenyl)-1-[3-(2-methoxyphenyl)-1H-indol-1-yl]-3-(methyl-
amino)propan-2-ol Hydrochloride
##STR00182##
[1389] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-methoxyphenyl]-1H-indol-1-yl}propane-1-
,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 2-methoxybenzeneboronic acid.
[1390] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(2-methoxyphenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-methoxyphenyl]-1H-indol-1-yl}propane-1-
,2-diol.
[1391] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-1-[3-(2-methoxyphenyl)-1H-indol-1-yl]-3-(methy-
lamino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(2-methoxyphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
405.1; HRMS: calcd for C25H25FN2O2+H+, 405.19728; found (ESI,
[M+H]+), 405.1984.
Example 177
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl)phenyl-
]-1H-indol-1-yl}propan-2-ol Hydrochloride
##STR00183##
[1393] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-(trifluoromethyl)phenyl]-1H-indol-1-yl-
}propane-1,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 3-(trifluoromethyl)benzeneboronic
acid.
[1394] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(3-(trifluoromethyl)phenyl)-indol-1-yl]-2-hydroxy-
-propyl ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[3-(trifluoromethyl)phenyl]-1H-indol-1-yl-
}propane-1,2-diol.
[1395] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl)pheny-
l]-1H-indol-1-yl}propan-2-ol hydrochloride was prepared
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(3-(trifluoromethyl)phenyl)-indol-1-yl]-2-hydroxy-
-propyl ester and methylamine (2N solution in methanol). MS (ESI)
m/z 443.1; HRMS: calcd for C25H22F4N2O+H+, 443.17410; found (ESI,
[M+H]+), 443.1764.
Example 178
(1S,2R)-3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00184##
[1397] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol was
prepared from 3-methylindole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as an
oil. MS (ESI) m/z 282 ([M+H].sup.+).
[1398] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-3-amino-1-(3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(3-methyl-indol-1-yl)-3-phenyl-propane-1,2-diol and
para-toluenesulfonic acid followed by concentrated ammonium
hydroxide as an off-white solid. MS (ESI) m/z 281.
Example 179
(1S,2R)-1-(7-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-
-2-ol Hydrochloride
##STR00185##
[1400] In an analogous manner to EXAMPLE 117, step 1 ethyl
7-fluoro-3-methyl-1H-indole-2-carboxylate was prepared from
2-fluoroaniline as a brownish solid. MS (ESI) m/z 221.
[1401] In an analogous manner to EXAMPLE 117, step 2
7-fluoro-3-methyl-1H-indole-2-carboxylic acid was prepared from
ethyl 7-fluoro-3-methyl-1H-indole-2-carboxylate as a green solid.
MS (ESI) m/z 192.
[1402] In an analogous manner to EXAMPLE 117, step 3
7-fluoro-3-methyl-1H-indole was prepared from
7-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS
(ESI) m/z 150.
[1403] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(7-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
was prepared from 7-fluoro-3-methyl-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, Step 4) as an
oil. MS (ESI) m/z 300.
[1404] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(7-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropa-
n-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
as a white solid. MS (ES) m/z 313.1.
Example 180
(1S,2R)-3-amino-1-(7-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
Hydrochloride
##STR00186##
[1406] In an analogous manner to EXAMPLE 117, step 6
3-amino-1-(7-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(7-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol
(EXAMPLE 179, step 4) and para-toluenesulfonic acid followed by
ammonium hydroxide as a white solid. MS (ES) m/z 299.0.
Example 181
(1S,2R)-1-(7-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00187##
[1408] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(7-fluoro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 7-fluoro-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, Step 4) as an
oil. MS (ES) m/z 286.1.
[1409] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(7-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(7-fluoro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
pinkish solid. MS (ESI) m/z 299.
Example 182
(1S,2R)-1-(4-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00188##
[1411] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(4-fluoro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 4-fluoro-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, Step 4) as an
oil. MS (ES) m/z 286.1.
[1412] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(4-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(4-fluoro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white solid. MS (ESI) m/z 299.
Example 183
(1S,2R)-1-(7-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00189##
[1414] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(7-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 7-fluoro-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, Step
3) as a brown oil. MS (ESI) m/z 304.
[1415] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(7-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(7-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a pinkish solid. MS (ESI) m/z 317.
Example 184
(1S,2R)-1-(4-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)propa-
n-2-ol Hydrochloride
##STR00190##
[1417] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(4-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 4-fluoro-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, Step
3) as a brown oil. MS (ESI) m/z 304.
[1418] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(4-fluoro-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)prop-
an-2-ol hydrochloride was prepared from
(2S,3S)-3-(4-fluoro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a white solid. MS (ESI) m/z 317.
Example 185
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indol-
-1-yl]propan-2-ol Hydrochloride
##STR00191##
[1420] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-fluorophenyl)-3-(5-trifluoromethyl-1H-indol-1-yl)-propane-1,-
2-diol was prepared from 5-trifluoromethyl-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, Step
3).
[1421] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indo-
l-1-yl]propan-2-ol hydrochloride was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(5-trifluoromethyl-1H-indol-1-yl)-propane-1,-
2-diol as an off-white solid. MS (ESI) m/z 367.
Example 186
(1S,2R)-1-(6-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00192##
[1423] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(6-fluoro-1H-indol-1-yl)-3-phenylpropane-1,2-diol was
prepared from 6-fluoro-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, Step 4) as a
brown oil. MS (ES) m/z 286.1.
[1424] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(6-fluoro-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(6-fluoro-1H-indol-1-yl)-3-phenylpropane-1,2-diol as a
white solid. MS (ESI) m/z 299.
Example 187
(1S,2R)-3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indol-1-yl]prop-
an-2-ol Hydrochloride
##STR00193##
[1426] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-phenyl-3-[6-(trifluoromethyl)-1H-indol-1-yl]propane-1,2-diol
was prepared from 6-trifluoromethyl-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, Step 4) as a
brown oil. MS (ES) m/z 336.
[1427] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indol-1-yl]pro-
pan-2-ol hydrochloride was prepared from
(2S,3S)-3-phenyl-3-[6-(trifluoromethyl)-1H-indol-1-yl]propane-1,2-diol
as a white solid. MS (ESI) m/z 349.
Example 188
(1S,2R)-3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indol-1-yl]prop-
an-2-ol Hydrochloride
##STR00194##
[1429] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-phenyl-3-[5-(trifluoromethyl)-1H-indol-1-yl]propane-1,2-diol
was prepared from 5-trifluoromethyl-1H-indole and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, Step 4) as a
brown oil. MS (ES) m/z 336.
[1430] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indol-1-yl]pro-
pan-2-ol hydrochloride was prepared from
(2S,3S)-3-phenyl-3-[5-(trifluoromethyl)-1H-indol-1-yl]propane-1,2-diol
as an off-white solid. MS (ESI) m/z 349.2.
Example 189
(1S,2R)-1-(3-tert-butyl-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)p-
ropan-2-ol
##STR00195##
[1432] Step 1: To a mixture of indole (5 g, 42.7 mmol), zinc
triflate (9.3 g, 25.6 mmol), and tetrabutylammonium iodide (7.9 g,
21.4 mmol) in anhydrous toluene (120 mL) was added
diisopropylethylamine (8.2 mL, 47 mmol) at room temperature under a
blanket of nitrogen. After the reaction was stirred 15 minutes at
room temperature, the reaction mixture was treated with tert-butyl
bromide (2.5 mL, 21.7 mmol). The reaction solution was stirred at
room temperature under nitrogen for 3 hours, then poured into a
saturated aqueous solution of ammonium chloride (150 mL). The
organic layer was separated and the aqueous layer was extracted
with ethyl acetate (3.times.50 mL). The combined organic layers
were dried over magnesium sulfate, concentrated, and the residue
was purified via flash column chromatography (silica, 10% ethyl
acetate in hexane) to afford 3-tert-butyl-1H-indole as a white
solid. MS (ES) m/z 174.2.
[1433] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-3-(3-tert-butyl-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
was prepared from 3-tert-butyl-1H-indole and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3).
[1434] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(3-tert-butyl-1H-indol-1-yl)-1-(3-fluorophenyl)-3-(methylamino)-
propan-2-ol was prepared from
(2S,3S)-3-(3-tert-butyl-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol
as a clear oil. MS (ESI) m/z 355.3.
Example 190
(1S,2R)-1-(1H-indol-1-yl)-2-methyl-3-(methylamino)-1-phenylpropan-2-ol
Hydrochloride
##STR00196##
[1436] In an analogous manner to EXAMPLE 117, step 4
[(2R,3R)-2-methyl-3-phenyloxiran-2-yl]methanol was prepared from
2-methyl-3-phenylprop-2-en-1-ol as a white crystal. MS (ES) m/z
147.1.
[1437] In an analogous manner to EXAMPLE 117, step 5
(2S,3S)-2-methyl-3-phenyl-[1H-indol-1-yl]propane-1,2-diol was
prepared from [(2R,3R)-2-methyl-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4) and indole
[1438] In an analogous manner to EXAMPLE 117, step 6
(1S,2R)-1-(1H-indol-1-yl)-2-methyl-3-(methylamino)-1-phenylpropan-2-ol
hydrochloride was prepared from
(2S,3S)-2-methyl-3-phenyl-[1H-indol-1-yl]propane-1,2-diol as a
white solid. MS (ES) m/z 295.0.
Example 191
(2R,3S)-3-(1H-indol-1-yl)-1-(methylamino)-3-phenylbutan-2-ol
Hydrochloride
##STR00197##
[1440] In an analogous manner to EXAMPLE 117, step 4
[(2R,3R)-3-methyl-3-phenyloxiran-2-yl]methanol was prepared from
3-methyl-3-phenylprop-2-en-1-ol as a white crystal. MS (ES) m/z
147.1.
[1441] In an analogous manner to EXAMPLE 47, step 4
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-phenylbutane-1,2-diol was
prepared from [(2R,3R)-3-methyl-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4) and indoline as a brown solid. MS (ES) m/z
284.1.
[1442] In an analogous manner to EXAMPLE 47, step 5
(2S,3S)-3-(1H-indol-1-yl)-3-phenylbutane-1,2-diol was prepared from
(2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-phenylbutane-1,2-diol as an
off-white solid. MS (ESI) m/z 282.
[1443] In an analogous manner to EXAMPLE 117, step 6
(2R,3S)-3-(1H-indol-1-yl)-1-(methylamino)-3-phenylbutan-2-ol
hydrochloride was prepared from
(2S,3S)-3-(1H-indol-1-yl)-3-phenylbutane-1,2-diol as a white solid.
MS (ES) m/z 295.1.
Example 192
1-tert-Butyl-3-(2-hydroxy-3-methylamino-1-phenyl-propyl)-1,3-dihydro-benzo-
imidazol-2-one Hydrochloride
##STR00198##
[1445] Step 1: To a solution of 1-fluoro-2-nitro-benzene (1 g, 7.1
mmol) in dimethylformamide (15 mL) was added tert-butyl amine (0.82
mL, 7.81 mmol) at room temperature, and the reaction mixture
stirred for 12 hours at room temperature under nitrogen. Upon
completion, the reaction mixture was poured into a saturated
aqueous solution of sodium chloride (50 mL) and extracted with
ethyl acetate (50 mL). The organic layer was dried over anhydrous
sodium sulfate, concentrated in vacuo, and the residue was purified
via flash column chromatography (silica, 1% ethyl acetate in
hexane) to give tert-butyl-(2-nitrophenyl)-amine as an orange oil.
MS (ES) m/z 195.2
[1446] Step 2: To a solution of tert-butyl-(2-nitrophenyl)-amine
(1.27 g, 6.5 mmol), 5% palladium on carbon (0.5 g), and sodium
borohydride (0.49 g, 13.1 mmol) in tetrahydrofuran (20 mL) was
added methanol (10 mL) in a dropwise manner. Upon completion of the
reaction, it was filtered through a pad of Celite and the filtrate
was poured into a saturated aqueous solution of ammonium chloride
(50 mL), and extracted with ethyl acetate (50 mL). The organic
layer was dried over anhydrous magnesium sulfate, concentrated in
vacuo to give N-tert-butyl-benzene-1,2-diamine which was used in
the next step without further purification. A solution of
N-t-butyl-benzene-1,2-diamine (1.1 g, 6.7 mmol) and
carbonyldiimidazole (1.63 g, 10 mmol) in anhydrous tetrahydrofuran
(50 mL) was stirred at room temperature for 12 hours. Upon
completion, the reaction was poured into a 1N aqueous solution of
hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL).
The organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude product was purified via flash
column chromatography (silica, 50% ethyl acetate in hexane) to give
1-tert-butyl-1,3-dihydro-benzimidazol-2-one as an off-white solid.
MS (ES) m/z 191.1.
[1447] Step 3: A mixture of
1-tert-butyl-1,3-dihydro-benzimidazol-2-one (0.66 g, 3.5 mmol) and
sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol) in
anhydrous dimethylformamide (4 mL) was stirred for 10 minutes under
nitrogen at room temperature. A solution of
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4, 1.07 g,
7.1 mmol) and titanium isopropoxide (2.14 mL, 7.1 mmol) in
dimethylformamide (4 mL) that was aged for 20 minutes was then
added and the mixture was stirred at room temperature under
nitrogen for 12 hours. After disappearance of the epoxide, the
mixture was partitioned between a 1N aqueous solution of
hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic
layer was separated, washed with saturated sodium bicarbonate (50
mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified via silica gel
column (60% ethyl acetate in hexane) to give
1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-ben-
zimidazol-2-one as an oil. MS (ES) m/z 341.2.
[1448] Step 4: A solution of
1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-ben-
zimidazol-2-one (0.55 g, 1.6 mmol) and para-toluenesulfonyl
chloride (0.37 g, 1.9 mmol) in anhydrous pyridine (5 mL) was
stirred at room temperature under nitrogen for 12 hours. The
reaction was poured into a cold 1N aqueous solution of hydrochloric
acid (50 mL) and extracted with ethyl acetate (50 mL). The organic
layer was dried over anhydrous sodium sulfate, filtered, and
concentrated to give (2S,3S)-toluene-4-sulfonic acid
3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phe-
nyl-propyl ester. To a solution of (2S,3S)-toluene-4-sulfonic acid
3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-p-
ropyl ester (0.8 g, 1.6 mmol) in methanol (10 mL) was added a 2N
solution of methylamine in methanol (4 mL, 8 mmol) and the reaction
mixture stirred for 12 hours at room temperature in a sealed tube.
Upon completion, the reaction was partitioned between a saturated
aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate
(50 mL). The organic layer was separated, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified via flash column chromatography (silica, 20% MeOH in
dichloromethane) to give
1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-methylamino-1-phenylpropyl]-1,3-dihyd-
ro-2H-benzimidazol-2-one as a clear oil. The free base was
dissolved in a minimum amount of ethanol and treated with a 2N
ethereal solution of hydrochloric acid and stirred for 1 hour s.
The ethanol was removed in vacuo and the clear oil was triturated
with diethyl ether/dichloromethane to give
1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-
-1,3-dihydro-2H-benzimidazol-2-one hydrochloride as a white solid.
HRMS: calcd for C.sub.21H.sub.27N.sub.3O.sub.2+H+, 354.21760; found
(ESI, [M+H].sup.+), 354.2179.
Example 193
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-propyl-1,3-dihydro--
2H-benzimidazol-2-one Hydrochloride
##STR00199##
[1450] In an analogous manner to EXAMPLE 192, step 1
2-nitro-N-propylaniline was prepared from 1-fluoro-2-nitro-benzene
and propyl amine. MS (ES) m/z 181.1.
[1451] In an analogous manner to EXAMPLE 192, step 2
1-propyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from
2-nitro-N-propylaniline. MS (ES) m/z 177.1.
[1452] In an analogous manner to EXAMPLE 192, step 3
1-propyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimi-
dazol-2-one was prepared from
1-propyl-1,3-dihydro-2H-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4).
[1453] In an analogous manner to EXAMPLE 192, step 4
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-propyl-1,3-dihydro-
-2H-benzimidazol-2-one hydrochloride was prepared from
1-propyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimi-
dazol-2-one as a white solid. HRMS: calcd for
C.sub.20H.sub.25N.sub.3O.sub.2+H+, 340.20195; found (ESI,
[M+H].sup.+), 340.2007
Example 194
5-bromo-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl--
1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00200##
[1455] Step 1: In an analogous manner to EXAMPLE 99, step 6
5-bromo-1-[(2S,3S)-2,3-dihydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-
-2H-indol-2-one was prepared from
5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one.sup.20 and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 391 ([M+H].sup.+). .sup.20WO 00/66166
[1456] Step 2: In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-2-hydroxy-3-phenyl--
propyl ester was prepared from
(5-bromo-1-[(2S,3S)-2,3-dihydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one). MS (ESI) m/z 545 ([M+H].sup.+).
[1457] Step 3: In an analogous manner to EXAMPLE 5
5-bromo-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-
-1,3-dihydro-2H-indol-2-one hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-2-hydroxy-3-phenyl--
propyl ester. MS m/z 404 ([M+H].sup.+), HRMS: calcd for
C20H23BrN2O2+H.sup.+, 403.10156; found (ESI, [M+H].sup.+),
403.0998.
Example 195
6-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-
-1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00201##
[1459] Step 1: In an analogous manner to EXAMPLE 99, step 2
dimethyl (4-fluoro-2-nitrophenyl)malonate was prepared from
2,5-difluoronitrobenzene and dimethyl malonate. MS (ESI) m/z 272
([M+H].sup.+).
[1460] Step 2: In an analogous manner to EXAMPLE 99, step 3
(4-fluoro-2-nitrophenyl)acetic acid was prepared from dimethyl
(4-fluoro-2-nitrophenyl)malonate. MS (ESI) m/z 200
([M+H].sup.+).
[1461] Step 3: In an analogous manner to EXAMPLE 99, step 4
6-fluoro-1,3-dihydro-2H-indol-2-one was prepared from
(4-fluoro-2-nitrophenyl)acetic acid. MS (ESI) m/z 152
([M+H].sup.+)
[1462] Step 4: In an analogous manner to EXAMPLE 99, step 5
6-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one was prepared from
6-fluoro-1,3-dihydro-2H-indol-2-one. MS (ESI) m/z 180
([M+H].sup.+.
[1463] Step 5: In an analogous manner to EXAMPLE 99, step 6
(2S,3S)-1-(2,3-dihydroxy-1-phenyl-propyl)-6-fluoro-3,3-dimethyl-1,3-dihyd-
ro-indol-2-one was prepared from
6-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 330 ([M+H].sup.+).
[1464] Step 6: In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-2-hydroxy-3-phenyl-
-propyl ester was prepared from
(2S,3S)-1-(2,3-dihydroxy-1-phenyl-propyl)-6-fluoro-3,3-dimethyl-1,3-dihyd-
ro-indol-2-one. MS (ESI) m/z 484 ([M+H].sup.+).
[1465] Step 7: A solution of (2S,3S)-toluene-4-sulfonic acid
3-(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-2-hydroxy-3-phenyl-
-propyl ester (367 mg, 0.76 mmol) and methylamine (20 mL, 8M
solution in ethanol) was stirred in a sealed tube for 16 hours. The
solution was concentrated in vacuo to give 250 mg of the crude
product. The crude product was purified via Biotage chromatography
(FlasH40i, silica, 5%, 8% and 10% methanol with
ammonia/dichloromethane) to give 77 mg of impure desired product.
Final purification by reverse phase HPLC(X-terra MS C.sub.18
19.times.150 mm, using an isocratic mixture of 60% methanol/water
with 0.05% ammonium hydroxide at a rate of 20 mL/minute at 250 nm)
gave 35 mg of desired product as the free base. The free base was
treated with a 1 M ethereal solution of hydrochloric acid until the
solution was pH=3 followed by diethyl ether. The product was
crystallized by adding a minimum of hexane to afford the title
compound
6-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one hydrochloride. MS (ESI) m/z 343
([M+H].sup.+); HRMS: calcd for C20H23FN2O2+H.sup.+, 343.18163;
found (ESI, [M+H].sup.+), 343.18.
Example 196
4-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimethyl-
-1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00202##
[1467] Step 1: In an analogous manner to EXAMPLE 99, step 1
1,2-difluoro-3-nitro-benzene was prepared from
2,3-Difluoro-phenylamine and a mixture of sodium perborate
tetrahydrate. MS (ESI) m/z 160 ([M+H].sup.+).
[1468] Step 2: In an analogous manner to EXAMPLE 99, step 2
dimethyl (2-fluoro-6-nitrophenyl) malonate was prepared from
1,2-difluoro-3-nitro-benzene. MS (ESI) m/z 272.0576.
[1469] Step 3: In an analogous manner to EXAMPLE 99, step 3
(2-fluoro-6-nitrophenyl)acetic acid was prepared from dimethyl
(2-fluoro-6-nitrophenyl)malonate. MS (ESI) m/z 200
([M+H].sup.+).
[1470] Step 4: In an analogous manner to EXAMPLE 99, step 4
4-fluoro-1,3-dihydro-2H-indol-2-one was prepared from
(2-fluoro-6-nitrophenyl)acetic acid. MS (ESI) m/z 152
([M+H].sup.+).
[1471] Step 5: In an analogous manner to EXAMPLE 99, step 5
4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one was prepared from
4-fluoro-1,3-dihydro-2H-indol-2-one. MS (ESI) m/z 180
([M+H].sup.+).
[1472] Step 6: In an analogous manner to EXAMPLE 99, step 6
1-[(2S,3S)-2,3-dihydroxy-1-phenylpropyl]-4-fluoro-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one was prepared from
4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ESI) m/z 330 ([M+H].sup.+).
[1473] Step 7: In an analogous manner to EXAMPLE 1 step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-2-hydroxy-3-phenyl-
-propyl ester was prepared from
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-4-fluoro-3,3-dimethyl-1,3-dihydr-
o-2H-indol-2-one. MS (ESI) m/z 484 ([M+H].sup.+.
[1474] Step 8: In an analogous manner to EXAMPLE 195 step
7,4-fluoro-1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3,3-dimet-
hyl-1,3-dihydro-2H-indol-2-one hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-2-hydroxy-3-phenyl-
-propyl ester. HRMS: calcd for C20H23FN2O2+H.sup.+, 343.18163;
found (ESI, [M+H].sup.+), 343.1807.
Example 197
1-cyclobutyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihy-
dro-2H-benzimidazol-2-one Hydrochloride
##STR00203##
[1476] In an analogous manner to EXAMPLE 192, step 1
N-cyclobutyl-2-nitroaniline was prepared from
1-fluoro-2-nitro-benzene and cyclobutyl amine. MS (ES) m/z 193.
[1477] In an analogous manner to EXAMPLE 192, step 2
1-cyclobutyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from
N-cyclobutyl-2-nitroaniline. MS (ES) m/z 189.
[1478] In an analogous manner to EXAMPLE 192, step 3
1-cyclobutyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-ben-
zimidazol-2-one was prepared from
1-cyclobutyl-1,3-dihydro-2H-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4). MS
(ES) m/z 339.2.
[1479] In an analogous manner to EXAMPLE 192, step 4
1-cyclobutyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dih-
ydro-2H-benzimidazol-2-one hydrochloride was prepared from
1-cyclobutyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-ben-
zimidazol-2-one as a white solid. MS (ES) m/z 352.2. HRMS: calcd
for C.sub.21H.sub.25N.sub.3O.sub.2+H+, 352.20195; found (ESI,
[M+H].sup.+), 352.207
Example 198
5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1-propyl-1,3-
-dihydro-2H-benzimidazol-2-one Hydrochloride
##STR00204##
[1481] In an analogous manner to EXAMPLE 192, step 1
(4-fluoro-2-nitro-phenyl)-propyl-amine was prepared from
1,4-difluoro-2-nitro-benzene and propyl amine.
[1482] In an analogous manner to EXAMPLE 192, steps 1 and 2
5-fluoro-1-propyl-1,3-dihydro-benzimidazol-2-one was prepared from
(4-fluoro-2-nitro-phenyl)-propyl-amine. MS (ES) m/z 195.2.
[1483] In an analogous manner to EXAMPLE 192, step 3
5-fluoro-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1-propyl-1,3-dihydro-2-
H-benzimidazol-2-one was prepared from
5-fluoro-1-propyl-1,3-dihydro-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4).
[1484] In an analogous manner to EXAMPLE 192, step 4
5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1-propyl-1,-
3-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from
5-fluoro-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1-propyl-1,3-dihydro-2-
H-benzimidazol-2-one as a white solid. MS (ES) m/z 358.2; HRMS:
calcd for C.sub.20H.sub.24FN.sub.3O.sub.2+H+, 358.19253; found
(ESI, [M+H].sup.+), 358.1895
Example 199
1-Ethyl-3-[1-(3-fluoro-phenyl)-2-hydroxy-3-methylamino-propyl]-1,3-dihydro-
-benzimidazol-2-one Hydrochloride
##STR00205##
[1486] Step 1: To a solution of ethylamine in methanol (2.0 M, 150
mL, 300 mmol) was added 1-fluoro-2-nitrobenzene (8 mL, 75.7 mmol).
The reaction mixture was placed in a sealed vessel and heated to
55.degree. C. for 15 hours. The solvent was removed in vacuo and
the residue was taken up in ethyl acetate (200 mL), washed with a
saturated aqueous solution of sodium bicarbonate (80 mL), and dried
over anhydrous sodium sulfate (50 g). After removal of solvent,
ethyl-(2-nitro-phenyl)-amine (12.5 g, 75 mmol) was obtained as a
brown oil. MS (ES) m/z 167.1.
[1487] Step 2: To a solution of ethyl-(2-nitro-phenyl)-amine (12.5
g, 75 mmol) in anhydrous tetrahydrofuran (150 mL) was added sodium
borohydride (5.8 g, 153 mmol), and 5% palladium on carbon (150 mg).
Methanol (25 mL) was then added at room temperature under nitrogen
in a dropwise manner. After addition, the reaction mixture was
stirred at room temperature for about 30 minutes until the reaction
was complete. The reaction mixture was then filtered through a pad
of Celite. The filtrate was diluted with ethyl acetate (200 mL),
washed with a saturated aqueous solution of ammonium chloride (80
mL), dried over sodium sulfite, and concentrated in vacuo to afford
crude N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol) which was used
in next step without further purification.
[1488] Step 3: To a solution of crude N-ethyl-benzene-1,2-diamine
(8.4 g, 62 mmol) in anhydrous tetrahydrofuran (200 mL) was added
1,1'-carbonyldiimidazole (10 g, 62 mmol). The mixture was stirred
at room temperature under nitrogen for 12 hours and ethyl acetate
(250 mL) followed by a cold 3N aqueous solution of hydrochloric
acid (200 mL) were added. The organic layer was separated, dried
over sodium sulfate and concentrated in vacuo to afford
1-ethyl-1,3-dihydro-benzimidazol-2-one as a white solid (8.5 g, 69%
for three steps). MS (ES) m/z 163.2.
[1489] Step 4: In an analogous manner to EXAMPLE 192, step 3
1-ethyl-3-[(1S,2S)-2,3-dihydroxy-1-(3-fluorophenyl)-propyl]-1,3-dihydro-2-
H-benzimidazol-2-one was prepared from
1-ethyl-1,3-dihydro-benzimidazol-2-one and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3).
[1490] Step 5: In an analogous manner to EXAMPLE 192, step 4
1-ethyl-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1,-
3-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from
1-ethyl-3-[(1S,2S)-2,3-dihydroxy-1-(3-fluorophenyl)-propyl]-1,3-dihydro-2-
H-benzimidazol-2-one as a white solid. MS (ES) m/z 344.2
Example 200
1-Ethyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2-
H-benzimidazol-2-one Hydrochloride
##STR00206##
[1492] In an analogous manner to EXAMPLE 192, step 3
1-ethyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimid-
azol-2-one was prepared from 1-ethyl-1,3-dihydro-benzimidazol-2-one
(EXAMPLE 199, step 2) and [(2R,3R)-3-phenyloxiran-2-yl]methanol
(EXAMPLE 117, step 4).
[1493] In an analogous manner to EXAMPLE 192, steps 4 and 5
1-ethyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro--
2H-benzimidazol-2-one hydrochloride was prepared from
1-ethyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimid-
azol-2-one as a white solid. MS (ES) m/z 326.2; HRMS: calcd for
C.sub.19H.sub.23N.sub.3O.sub.2+H+, 326.18630; found (ESI,
[M+H].sup.+), 326.1845.
Example 201
4-Fluoro-3-(2-hydroxy-3-methylamino-1-phenyl-propyl)-1-isopropyl-1,3-dihyd-
ro-benzimidazol-2-one Hydrochloride
##STR00207##
[1495] In an analogous manner to EXAMPLE 192, step 1
(3-fluoro-2-nitro-phenyl)-isopropyl-amine was prepared from
1,3-difluoro-2-nitro-benzene and iso-propylamine.
[1496] In an analogous manner to EXAMPLE 192, step 2
4-fluoro-1-isopropyl-1,3-dihydro-benzimidazol-2-one was prepared
from (3-fluoro-2-nitro-phenyl)-isopropyl-amine. MS (ES) m/z
195.2.
[1497] In an analogous manner to EXAMPLE 192, step 3
4-fluoro-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1-isopropyl-1,3-dihydr-
o-2H-benzimidazol-2-one was prepared from
4-fluoro-1-isopropyl-1,3-dihydro-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4).
[1498] In an analogous manner to EXAMPLE 192, step 4
4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1-isopropyl-
-1,3-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from
4-fluoro-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1-isopropyl-1,3-dihydr-
o-2H-benzimidazol-2-one as a white solid. MS (ES) m/z 358.4.
Example 202
1-Cyclopentyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dih-
ydro-2H-benzimidazol-2-one Hydrochloride
##STR00208##
[1500] In an analogous manner to EXAMPLE 192, step 1
N-cyclopentyl-2-nitroaniline was prepared from
1-fluoro-2-nitro-benzene and cyclopentyl amine. MS (ESI) m/z
207.
[1501] In an analogous manner to EXAMPLE 192, step 2
1-cyclopentyl-1,3-dihydro-benzimidazol-2-one was prepared from
N-cyclopentyl-2-nitroaniline. MS (ESI) m/z 203.
[1502] In an analogous manner to EXAMPLE 192, step 3
1-cyclopentyl-3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1,3-dihydro-2H-ben-
zimidazol-2-one was prepared from
1-cyclopentyl-1,3-dihydro-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid. MS (ES) m/z 352.9.
[1503] In an analogous manner to EXAMPLE 192, step 4
1-cyclopentyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-di-
hydro-2H-benzimidazol-2-one hydrochloride was prepared from
1-cyclopentyl-3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1,3-dihydro-2H-ben-
zimidazol-2-one as a white solid. MS (ES) m/z MS (ESI) m/z 366.
Example 203
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-isopropyl-1,3-dihyd-
ro-2H-benzimidazol-2-one Hydrochloride
##STR00209##
[1505] In an analogous manner to EXAMPLE 192, step 1
N-isopropyl-2-nitroaniline was prepared from
1-fluoro-2-nitro-benzene and isopropyl amine. MS (ES) m/z
181.2.
[1506] In an analogous manner to EXAMPLE 192, step 2
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from
N-isopropyl-2-nitroaniline. MS (ES) m/z 176.9.
[1507] In an analogous manner to EXAMPLE 192, step 3
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3-isopropyl-1,3-dihydro-2H-benzi-
midazol-2-one was prepared from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid.
[1508] In an analogous manner to EXAMPLE 192, step 4
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-isopropyl-1,3-dihy-
dro-2H-benzimidazol-2-one hydrochloride was prepared from
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3-isopropyl-1,3-dihydro-2H-benzi-
midazol-2-one as a white solid. MS (ES) m/z MS (ES) m/z 340.3;
HRMS: calcd for C.sub.20H.sub.25N.sub.3O.sub.2+H+, 340.20195; found
(ESI, [M+H].sup.+), 340.2012.
Example 204
3-[(1S,2R)-3-(ethylamino)-2-hydroxy-1-phenylpropyl]-5-fluoro-1-isopropyl-1-
,3-dihydro-2H-benzimidazol-2-one Hydrochloride
##STR00210##
[1510] In an analogous manner to EXAMPLE 192, step 1
4-fluoro-N-isopropyl-2-nitroaniline was prepared from
1,4-difluoro-2-nitro-benzene and isopropyl amine. MS (ES) m/z
199.1.
[1511] In an analogous manner to EXAMPLE 192, step 2
5-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one was prepared
from 4-fluoro-N-isopropyl-2-nitroaniline. MS (ES) m/z 195.1.
[1512] In an analogous manner to EXAMPLE 192, step 3
5-fluoro-1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3-isopropyl-1,3-dihydro-
-2H-benzimidazol-2-one was prepared from
5-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid.
[1513] In an analogous manner to EXAMPLE 192, step 4
3-[(1S,2R)-3-(ethylamino)-2-hydroxy-1-phenylpropyl]-5-fluoro-1-isopropyl--
1,3-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from
5-fluoro-1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3-isopropyl-1,3-dihydro-
-2H-benzimidazol-2-one and para-toluenesulfonic acid followed by
ethylamine as a white solid. MS (ESI) m/z 372.21; HRMS: calcd for
C.sub.21H.sub.26FN.sub.3O.sub.2+H+, 372.20818; found (ESI,
[M+H].sup.+), 372.2099.
Example 205
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-methyl-1,3-dihydro--
2H-benzimidazol-2-one Hydrochloride
##STR00211##
[1515] In an analogous manner to EXAMPLE 192, step 3
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3-methyl-1,3-dihydro-2H-benzimid-
azol-2-one was prepared from
1-methyl-1,3-dihydro-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid.
[1516] In an analogous manner to EXAMPLE 192, step 4
1-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-3-methyl-1,3-dihydro-
-2H-benzimidazol-2-one hydrochloride was prepared from
1-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-3-methyl-1,3-dihydro-2H-benzimid-
azol-2-one as a white solid. MS (ES) m/z 312.3; HRMS: calcd for
C.sub.18H.sub.21N.sub.3O.sub.2+H+, 312.17065; found (ESI,
[M+H].sup.+), 312.17.
Example 206
1-Ethyl-5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3--
dihydro-2H-benzimidazol-2-one Hydrochloride
##STR00212##
[1518] In an analogous manner to EXAMPLE 199, step 1
ethyl-(4-fluoro-2-nitro-phenyl)-amine was prepared from
1,4-difluoro-2-nitroaniline and ethylamine.
[1519] In an analogous manner to EXAMPLE 199, step 2
N-ethyl-4-fluoro-benzene-1,2-diamine was prepared from
ethyl-(4-fluoro-2-nitro-phenyl)-amine.
[1520] In an analogous manner to EXAMPLE 199, step 3
1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one was prepared
from N-ethyl-4-fluoro-benzene-1,2-diamine. MS (ES) m/z 181.2.
[1521] In an analogous manner to EXAMPLE 192, step 3
3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1-ethyl-5-fluoro-1,3-dihydro-2H--
benzimidazol-2-one was prepared from
1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid. MS (ES) m/z 331.1.
[1522] In an analogous manner to EXAMPLE 192, step 4
1-ethyl-5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-
-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from
3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1-ethyl-5-fluoro-1,3-dihydro-2H--
benzimidazol-2-one as a white solid. MS (ES) m/z 344.2; HRMS: calcd
for C.sub.19H.sub.22FN.sub.3O.sub.2+H+, 344.17688; found (ESI,
[M+H].sup.+), 344.175.
Example 207
1-Ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3--
dihydro-2H-benzimidazol-2-one Hydrochloride
##STR00213##
[1524] In an analogous manner to EXAMPLE 199, step 1
ethyl-(3-fluoro-2-nitro-phenyl)-amine was prepared from
1,3-difluoro-2-nitroaniline and ethylamine.
[1525] In an analogous manner to EXAMPLE 199, step 2
N-ethyl-3-fluoro-benzene-1,2-diamine was prepared from
ethyl-(3-fluoro-2-nitro-phenyl)-amine.
[1526] In an analogous manner to EXAMPLE 199, step 3
1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one was prepared
from N-ethyl-3-fluoro-benzene-1,2-diamine. MS (ES) m/z 181.2.
[1527] In an analogous manner to EXAMPLE 192, step 3
3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1-ethyl-4-fluoro-1,3-dihydro-2H--
benzimidazol-2-one was prepared from
1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one and
[(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4) as a
white solid. MS (ES) m/z 331.1.
[1528] In an analogous manner to EXAMPLE 192, step 4
1-ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-
-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from
3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1-ethyl-4-fluoro-1,3-dihydro-2H--
benzimidazol-2-one as a white solid. MS (ES) m/z 344.2; HRMS: calcd
for C.sub.19H.sub.22FN.sub.3O.sub.2+H+, 344.17688; found (ESI,
[M+H].sup.+), 344.1768.
Example 208
4-fluoro-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)-propyl]-1-
-isopropyl-1,3-dihydro-2H-benzimidazol-2-one Hydrochloride
##STR00214##
[1530] In an analogous manner to EXAMPLE 192, step 3
4-fluoro-3-[(1S,2S)-1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-1-isopropyl-
-1,3-dihydro-benzimidazol-2-one was prepared from
4-fluoro-1-isopropyl-1,3-dihydro-benzimidazol-2-one (EXAMPLE 201,
step 2) and [(2R,3R)-3-(3-fluorophenyl)-oxiran-2-yl]methanol
(EXAMPLE 47, step 3) as an oil.
[1531] In an analogous manner to EXAMPLE 192, step 4
4-fluoro-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)-propyl]--
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride was
prepared from
4-fluoro-3-[(1S,2S)-1-(3-fluorophenyl)-2,3-dihydroxy-propyl]-1-isopr-
opyl-1,3-dihydro-benzimidazol-2-one as a white solid. MS (ES) m/z
376.2
Example 209
1-Ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-(3-fluorophenyl)-p-
ropyl]-1,3-dihydro-2H-benzimidazol-2-one Hydrochloride
##STR00215##
[1533] In an analogous manner to EXAMPLE 192, step 3
3-[(1S,2S)-2,3-dihydroxy-1-(3-fluorophenyl)-propyl]-1-ethyl-4-fluoro-1,3--
dihydro-2H-benzimidazol-2-one was prepared from
1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one (EXAMPLE 207,
step 2) and [(2R,3R)-3-(3-fluorophenyl)-oxiran-2-yl]methanol
(EXAMPLE 47, step 3) as clear oil. MS (ES) m/z 349.1.
[1534] In an analogous manner to EXAMPLE 192, step 4
1-ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-(3-fluorophenyl)--
propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride was
prepared from
3-[(1S,2S)-2,3-dihydroxy-1-(3-fluorophenyl)-propyl]-1-ethyl-4-fluoro-1,3--
dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m/z
362.1.
Example 210
1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimethy-
l-1,3-dihydro-2H-indol-2-one Hydrochloride
##STR00216##
[1536] Step 1: In an analogous manner to EXAMPLE 101, step 1
(2S,3S)-1-[1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-3,3-dimethyl-1,3-dih-
ydro-indol-2-one was prepared from
3,3-dimethyl-1,3-dihydro-indol-2-one.sup.10 and
[(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step
3). MS (ESI) m/z 330 ([M+H].sup.+).
[1537] Step 2: In an analogous manner to EXAMPLE 1, step 2
(2S,3S)-toluene-4-sulfonic acid
3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-3-(3-fluoro-phenyl)-2-hydro-
xy-propyl ester was prepared from
(2S,3S)-1-[1-(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-3,3-dimethyl-1,3-dih-
ydro-indol-2-one. MS (ESI) m/z 484 ([M+H].sup.+).
[1538] Step 3: In an analogous manner to EXAMPLE 5
1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimeth-
yl-1,3-dihydro-2H-indol-2-one hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-3-(3-fluoro-phenyl)-2-hydro-
xy-propyl ester. MS (ESI) m/z 343 ([M+H].sup.+).
Example 211
(1S,2R)-1-[3-(2,3-difluorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(met-
hylamino)propan-2-ol Hydrochloride
##STR00217##
[1540] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-[3-(2,3-difluorophenyl)-1H-indol-1-yl]propane--
1,2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 2,3-difluorobenzeneboronic acid.
[1541] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-(2,3-difluorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-[3-(2,3-difluorophenyl)-1H-indol-1-yl]propan-
e-1,2-diol.
[1542] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-[3-(2,3-difluorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(me-
thylamino)propan-2-ol was prepared from (2S,3S)-toluene-4-sulfonic
acid
3-(3-fluorophenyl)-3-(2,3-difluorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester. MS (ES) m/z 411.1; HRMS: calcd for C24H21F3N2O+H+,
411.16787; found (ESI, [M+H]+), 411.1675.
Example 212
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-
-1,4-benzoxazin-4-yl]propan-2-ol Hydrochloride
##STR00218##
[1544] Step 1: Diastereomeric mixture of
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-
-benzoxazin-4-yl)propan-2-ol (EXAMPLE 168) was dissolved in
methanol. The resulting solution was injected onto the
Supercritical Fluid Chromatography instrument. The baseline
resolved diastereomers, using the conditions described below, were
collected. [1545] SFC Instrument: Berger MultiGram Prep SFC (Berger
Instruments, Inc. Newark, Del. 19702. [1546] Column: Ethyl
pyridine; 250 mm L.times.20 mm ID (Princeton Chromatography Inc.)
[1547] Column temperature: 35.degree. C. [1548] SFC Modifier: 15%
MeOH with 85% CO.sub.2 [1549] Flow rate: 50 mL/min [1550] Outlet
Pressure: 100 bar [1551] Detector: UV at 220 nm
[1552] Step 2:
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4-
H-1,4-benzoxazin-4-yl]propan-2-ol, isolated as peak 1, was
subjected to hydrochloride salt formation in an analogous manner to
EXAMPLE 144, step 2 to give
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-
-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol hydrochloride as a
white powder. MS (ES) m/z 393.2 ([M+H].sup.+); HRMS: calcd for
C.sub.24H.sub.25FN.sub.2O.sub.2+H.sup.+, 393.1973; found (ESI,
[M+H].sup.+), 393.1992.
Example 213
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-
-1,4-benzoxazin-4-yl]propan-2-ol Hydrochloride
##STR00219##
[1554] In an analogous manner to EXAMPLE 212,
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4-
H-1,4-benzoxazin-4-yl]propan-2-ol hydrochloride was prepared as a
white powder from
(1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4-
H-1,4-benzoxazin-4-yl]propan-2-ol, which was isolated as peak 2 of
the diastereomeric separation (EXAMPLE 212, step 1). MS (ES) m/z
393.2 ([M+H].sup.+); HRMS: calcd for
C.sub.24H.sub.25FN.sub.2O.sub.2+H.sup.+, 393.1973; found (ESI,
[M+H].sup.+), 393.1982.
Example 214
(1S,2R)-1-[3-(2-chlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methyla-
mino)propan-2-ol Hydrochloride
##STR00220##
[1556] In an analogous manner to EXAMPLE 114, step 2,
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-chlorophenyl]-1H-indol-1-yl}propane-1,-
2-diol was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol
(EXAMPLE 114, step 1) and 2-chlorobenzeneboronic acid.
[1557] In an analogous manner to EXAMPLE 1, step 2,
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluorophenyl)-3-[3-(2-chlorophenyl)-indol-1-yl]-2-hydroxy-propyl
ester was prepared from
(2S,3S)-3-(3-fluorophenyl)-3-{3-[2-chlorophenyl]-1H-indol-1-yl}propane-1,-
2-diol.
[1558] In an analogous manner to EXAMPLE 5,
(1S,2R)-1-[3-(2-chlorophenyl)-1H-indol-1-yl]-1-(3-fluorophenyl)-3-(methyl-
amino)propan-2-ol hydrochloride was prepared from
(2S,3S)-toluene-4-sulfonic acid
3-(3-fluoro-phenyl)-3-[3-(2-chlorphenyl)-indol-1-yl]-2-hydroxy-propyl
ester and methylamine (2N solution in methanol). MS (ESI) m/z
409.1; HRMS: calcd for C24H22ClFN2O+H+, 409.14774; found (ESI,
[M+H]+), 409.146.
[1559] Cell Lines, Culture Reagents, and Assays
[1560] MDCK-Net6 cells, stably transfected with human hNET
(Pacholczyk, T., R.D. Blakely, and S.G. Amara, Nature, 1991,
350(6316): p. 350-4) were cultured in growth medium containing high
glucose DMEM (Gibco, Cat. No. 11995), 10% FBS (dialyzed,
heat-inactivated, US Bio-Technologies, Lot FBD1129HI) and 500
.quadrature.g/ml G418 (Gibco, Cat. No. 10131). Cells were plated at
300,000/T75 flask and cells were split twice weekly. The JAR cell
line (human placental choriocarcinoma) was purchased from ATCC
(Cat. No. HTB-144). The cells were cultured in growth medium
containing RPMI 1640 (Gibco, Cat. No. 72400), 10% FBS (Irvine, Cat.
No. 3000), 1% sodium pyruvate (Gibco, Cat. No. 1136) and 0.25%
glucose. Cells were plated at 250,000 cells/T75 flask and split
twice weekly. For all assays, cells were plated in Wallac 96-well
sterile plates (PerkinElmer, Cat. No. 3983498).
[1561] Norepinephrine (NE) UPtake Assay
[1562] On day 1, cells were plated at 3,000 cells/well in growth
medium and maintained in a cell incubator (37.degree. C., 5%
CO.sub.2). On day 2, growth medium was replaced with 200 .mu.l of
assay buffer (25 mM HEPES; 120 mM NaCl; 5 mM KCl; 2.5 mM
CaCl.sub.2; 1.2 mM MgSO.sub.4; 2 mg/ml glucose (pH 7.4, 37.degree.
C.)) containing 0.2 mg/ml ascorbic acid and 10 .mu.M pargyline.
Plates containing cells with 200 .mu.l of assay buffer were
equilibrated for 10 minutes at 37.degree. C. prior to addition of
compounds. A stock solution of desipramine was prepared in DMSO (10
mM) and delivered to triplicate wells containing cells for a final
test concentration of 1 .mu.M. Data from these wells were used to
define non-specific NE uptake (minimum NE uptake). Test compounds
were prepared in DMSO (10 mM) and diluted in assay buffer according
to test range (1 to 10,000 nM). Twenty-five microliters of assay
buffer (maximum NE uptake) or test compound were added directly to
triplicate wells containing cells in 200 .mu.l of assay buffer. The
cells in assay buffer with test compounds were incubated for 20
minutes at 37.degree. C. To initiate the NE uptake, [.sup.3H]NE
diluted in assay buffer (120 nM final assay concentration) was
delivered in 25 .mu.l aliquots to each well and the plates were
incubated for 5 minutes (37.degree. C.). The reaction was
terminated by decanting the supernatant from the plate. The plates
containing cells were washed twice with 200 .mu.l assay buffer
(37.degree. C.) to remove free radioligand. The plates were then
inverted, left to dry for 2 minutes, then reinverted and air-dried
for an additional 10 minutes. The cells were lysed in 25 .mu.l of
0.25 N NaOH solution (4.degree. C.), placed on a shake table and
vigorously shaken for 5 minutes. After cell lysis, 75 .mu.l of
scintillation cocktail was added to each well and the plates were
sealed with film tape. The plates were returned to the shake table
and vigorously shaken for a minimum of 10 minutes to ensure
adequate partitioning of organic and aqueous solutions. The plates
were counted in a Wallac Microbeta counter (PerkinElmer) to collect
the raw cpm data.
[1563] Serotonin (5-HT) Uptake Assay
[1564] The methods for 5-HT functional reuptake using the JAR cell
line were modified using a previous literature report (Prasad, et
al., Placenta, 1996. 17(4): 201-7). On day 1, cells were plated at
15,000 cells/well in 96-well plates containing growth medium (RPMI
1640 with 10% FBS) and maintained in a cell incubator (37.degree.
C., 5% CO.sub.2). On day 2, cells were stimulated with
staurosporine (40 nM) to increase the expression of the 5-HT
transporter [17]. On day 3, cells were removed from the cell
incubator two hours prior to assay and maintained at room
temperature to equilibrate the growth medium to ambient oxygen
concentration. Subsequently, the growth medium was replaced with
200 .mu.l of assay buffer (25 mM HEPES; 120 mM NaCl; 5 mM KCl; 2.5
mM CaCl.sub.2; 1.2 mM MgSO.sub.4; 2 mg/ml glucose (pH 7.4,
37.degree. C.)) containing 0.2 mg/ml ascorbic acid and 10 .mu.M
pargyline. A stock solution of paroxetine (AHR-4389-1) was prepared
in DMSO (10 mM) and delivered to triplicate wells containing cells
for a final test concentration of 1 .mu.M. Data from these wells
were used to define non-specific 5-HT uptake (minimum 5-HT uptake).
Test compounds were prepared in DMSO (10 mM) and diluted in assay
buffer according to test range (1 to 1,000 nM). Twenty-five
microliters of assay buffer (maximum 5-HT uptake) or test compound
were added directly to triplicate wells containing cells in 200
.mu.l of assay buffer. The cells were incubated with the compound
for 10 minutes (37.degree. C.). To initiate the reaction,
[.sup.3H]hydroxytryptamine creatinine sulfate diluted in assay
buffer was delivered in 25 .mu.l aliquots to each well for a final
test concentration of 15 nM. The cells were incubated with the
reaction mixture for 5 minutes at 37.degree. C. The 5-HT uptake
reaction was terminated by decanting the assay buffer. The cells
were washed twice with 200 .mu.l assay buffer (37.degree. C.) to
remove free radioligand. The plates were inverted and left to dry
for 2 minutes, then reinverted and air-dried for an additional 10
minutes. Subsequently, the cells were lysed in 25 .mu.l of 0.25 N
NaOH (4.degree. C.) then placed on a shaker table and shaken
vigorously for 5 minutes. After cell lysis, 75 .mu.l of
scintillation cocktail was added to the wells, the plates were
sealed with film tape and replaced on the shake table for a minimum
of 10 minutes. The plates were counted in a Wallac Microbeta
counter (PerkinElmer) to collect the raw cpm data.
[1565] Evaluation of Results
[1566] For each experiment, a data stream of cpm values collected
from the Wallac Microbeta counter was downloaded to a Microsoft
Excel statistical application program. Calculations of EC.sub.50
values were made using the transformed-both-sides logistic dose
response program written by Wyeth Biometrics Department. The
statistical program uses mean cpm values from wells representing
maximum binding or uptake (assay buffer) and mean cpm values from
wells representing minimum binding or uptake ((1 .mu.M desipramine
(hNET) or 1 .mu.M paroxetine (hSERT)). Estimation of the EC.sub.50
value was completed on a log scale and the line was fit between the
maximum and minimum binding or uptake values. All graphic data
representation was generated by normalizing each data point to a
mean percent based on the maximum and minimum binding or uptake
values. The EC.sub.50 values reported from multiple experiments
were calculated by pooling the raw data from each experiment and
analyzing the pooled data as one experiment. The results are
reported in Table 1.
TABLE-US-00001 TABLE 1 Example % Inhibition @ 1 .mu.M (hNET) 1 4.6
2 66.5 (@ 10 .mu.M) 3 17.6 4 24.5 5 58.1 6 13.1 7 25.6 8 53.4 9
79.2 (@ 10 .mu.M) 10 70.5 (@ 10 .mu.M) 11 94.5 12 70.6 13 34.3 14
24.4 15 8.5 16 96.8 17 71.0 18 11.3 19 31.6 20 85.0 21 97.5 22 83.8
23 89.7 24 57.2 25 37.5 26 54.0 27 75.4 28 30.1 29 89.5 30 79.7 31
98.9 33 99.4 34 78.4 35 94.3 36 82.3 37 21.4 38 71.9 39 57.4 40
57.6 41 32.4 42 95.7 43 99 44 98.2 47 99.9 48 96.6 49 101.2 50 91.8
51 87.0 52 94.3 53 57.4 54 68.6 55 61.1 56 12.3 57 17.5 58 26.5 59
93.2 60 100 61 99.8 62 99.7 63 91.9 64 99.9 65 100 66 86.6 67 90.9
68 99.6 69 87.5 70 77.7 71 44.9 72 24 73 21.8 74 67 75 88.4 76 75.2
77 77.3 78 70.9 79 66 80 83.5 81 58.0 82 53.9 83 99.5 84 40.9 85
97.4 86 52.7 87 99.7 90 73.1 91 90.8 92 85.8 93 96.3 94 94.9 95
97.6 96 98.2 97 99.6 98 99.1 99 98.1 100 94.2 101 98.6 102 95.3 103
86.1 104 99.4 105 92.6 106 85.8 107 96.6 108 98.7 109 94.7 110 86.4
111 42.7 112 100.3 113 99.7 114 100 115 23.9 116 97.3 117 95.3 118
67.9 119 96.3 120 68.6 121 21.2 122 97.4 123 65 124 91.5 125 94.3
126 92.9 127 95.7 128 45.6 129 71.8 130 76 131 63.1 132 93 133 96.4
134 68.5 135 99.5 136 97 137 99.1 138 97.9 139 94.9 140 96.7 143
96.8 146 97.1 147 91.7 148 97.8 149 100.4 150 98.3 151 94.3 152
96.2 153 97.4 154 96.1 155 98.9 157 99.6 158 99.6 159 93.8 160 99.3
161 99.4 162 99.2 163 99.7 164 98.6 169 72 170 96.4 171 98.3 172 88
173 67.5 174 99.1 175 99.6 176 100 177 29.9 178 69.2 179 99.8 180
70.4 181 96.9 182 97.1 183 100.5 184 99.7 185 80.8 186 96.6 187 52
188 71.6 189 99.3 190 53.7 191 63.9 192 54.6 193 98.4 194 79 195 91
196 94.6 197 97 198 97.7 199 99.1 200 97.9 201 98.8 202 92.7 203
98.9 204 47.4 205 82.9 206 96.9 207 98.3 208 99.8 209 99.3 210 96.3
211 99.8 214 99.9
[1567] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges specific
embodiments therein are intended to be included.
[1568] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in its entirety.
[1569] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *